Methods and Compositions to Modulate RNA Processing

Abstract

The present disclosure provides methods and compositions to selectively modulate RNA processing. The methods and compositions selectively enhance or repress RNA processing by up- or down-regulating Drosha expression and/or by providing RNA sequences with mismatches introduced or removed 5 and/or 9-12 nucleotide positions from the Drosha cutting site. Therapeutic uses of the methods and compositions are also described.

Description

FIELD OF THE DISCLOSURE

The present disclosure provides methods and compositions to selectively modulate RNA processing. The methods and compositions selectively enhance or repress RNA processing by up- or down-regulating Drosha expression and/or by providing RNA sequences with mis-matches introduced or removed 5 and/or 9-12 nucleotide positions from the Drosha cutting site. Therapeutic uses of the methods and compositions are also described.

BACKGROUND OF THE DISCLOSURE

Generally, for a protein to exert an effect, the cell that will use or secrete the protein must create it. To create a protein the cell first makes a copy of the protein's gene sequence in the nucleus of the cell. This copy of the gene sequence that encodes for the protein (called messenger RNA (“mRNA”)) leaves the nucleus and is trafficked to a region of the cell containing ribosomes. Ribosomes read the sequence of the mRNA and create the protein for which it encodes. This process of new protein synthesis is known as translation. A variety of factors affect the rate and efficiency of protein translation. Among the most significant of these factors is the intrinsic stability of the mRNA itself. If the mRNA is degraded quickly within the cell (such as before it reaches a ribosome), it is unable to serve as a template for new protein translation, thus reducing the cell's ability to create the protein for which it encoded.

MicroRNAs (miRNA which also include isomiRs) are a group of short, non-coding RNAs that bind target mRNAs to either inhibit their translation or reduce their stability. miRNAs are transcribed in the nucleus as part of a primary microRNA (pri-miRNA). The length of pri-miRNAs is highly variable, ranging from ˜200 up to several thousand nucleotides (nt). pri-miRNAs are cleaved by the cellular Microprocessor complex, which consists of several components, principally Drosha and DGCR8. Drosha and DGCR8 cooperatively bind pri-miRNA, and Drosha cleaves the primary pri-miRNA transcript at ˜11 base pairs from the base of the stem-loop, liberating a structure known as the precursor microRNA (pre-miRNA).

pre-miRNA is ˜60-70 nt in length and forms a frequently mismatched hairpin structure with a 2 nt 3′ overhang. The pre-miRNA is transported from the nucleus to the cytoplasm and is subsequently cleaved by the enzyme Dicer with its cofactor trans-activator RNA (tar)-binding protein (TRBP). Dicer binds the 3′-overhang and cleaves the pre-miRNA ˜22 nt from the Drosha-cutting site to remove the terminal loop resulting in an imperfect ˜22 nt miRNA/miRNA* duplex. The miRNA enters the RNA-induced silencing complex (RISC), whereas the miRNA* strand is degraded. While the Drosha and Dicer processing mechanisms are described in relation to miRNA, the same mechanisms can process various other RNA types as well including mRNA.

RNAs, including miRNAs, are involved with the onset of various diseases, immunoregulation, neural growth and stem cell renewal and maintenance. RNA levels can be regulated in several ways. For example, pri-miRNA transcription is regulated by common DNA transcription factors, e.g. c-Myc. The Microprocessor complex contains several components besides Drosha and DGCR8, such as the DEAD-box helicases p68 and p72, which have been proposed to stabilize the Microprocessor complex. Other components of the Microprocessor include SMAD proteins which have been found to selectively upregulate certain RNAs, e.g. mir-21. The DGCR8 mRNA has stem loop structures that can be cleaved by the Microprocessor, accordingly giving DGCR8 a self regulating mechanism.

SUMMARY OF THE DISCLOSURE

The current disclosure provides methods and compositions to selectively enhance or repress RNA processing by up- or down-regulating Drosha expression and/or by providing RNA sequences with mis-matches introduced or removed 5 and/or 9-12 nucleotide (nt) positions from the Drosha cutting site. Particularly, the disclosure shows that altered Drosha expression levels can selectively regulate RNAs with particular secondary structures. More particularly, the current disclosure shows that RNA with fewer mismatches located 5 nt and/or 9-12 nt from the Drosha cutting site show greater resilience to reduced Drosha expression (i.e., their cleavage is less affected by reduced Drosha expression). On the other hand, RNA with more mismatches 5 nt and/or 9-12 nt from the Drosha cutting site show reduced cleavage (decreased levels) when Drosha levels are reduced and are thus less resilient to reduced Drosha expression. The current disclosure also shows that Drosha expression fluctuates during development and across different cell types. Understanding this novel mechanism of RNA regulation as well as the fluctuating levels of Drosha expression during development and across cell types allows one to up- or down-regulate Drosha expression to affect RNAs that are expressed within a cell. Conversely or in addition, one can predict changed RNA expression during development and/or in particular cell types and can selectively up- or down-regulate RNA during times of low or high natural expression. The current disclosure also provides for the strategic design of RNAs that can be more or less resilient to changing Drosha expression. Each of these mechanisms provide avenues for intelligent therapeutic design.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Fold change of miRNA expression between Drosha knockdown and control H1 hESC for 220 miRNAs assayed by qPCR. Arrow marks median (0.495).

FIG. 2. Fold change of expression for miRNAs between Drosha knockdown and Control H1 hESC for 220 miRNAs assayed by qPCR and grouped by genomic origin (intergenic/intronic).

FIG. 3A-C. Counting of mismatches in miRNAs in H1 cells with DroshaKD and control cells. Positions regarded as mismatched are marked by numerals in light grey (FIG. 3A). Mismatches summed for positions counted from the Drosha cutting site for a set of 202 miRNAs split in two equal groups based on fold change in the Drosha knockdown (FIG. 3B). P-values were calculated using Pearson's Chi-squared test with Yates' continuity correction, giving log p-values <−2 for positions 5, 10, 11 and 12 for the full data set split in half (dark grey) and for the quartiles at the extreme ends with sample size extrapolated to that of the full data set (FIG. 3C).

FIG. 4A-H. Differential expression of Drosha in mouse tissues. Expression levels in Drosha in mouse tissues, normalized to EEF2; GEO(GDS3052) (FIG. 4A), GEO(GDS3142) (FIG. 4B). Fold change of Drosha expression in liver, compared to the average expression of EEF2, RPL13A, SDHA, TBO and UBC; GDS3052 (FIG. 4C), GDS3142 (FIG. 4D). qPCR analysis of Drosha mRNA levels in mouse brain and liver (FIG. 4E), Quantification of Drosha protein levels show 9.6 fold increase in brain compared to liver tissue (p<0.05) (FIG. 4F), Western blot of Drosha protein in mouse brain and liver normalized to total protein (Coomassie Blue) (FIG. 4G), Geometric mean of clone counts of miRNAs with 1, 2, 3, 4 and 5 mismatches in the positions 5, 9-12 nucleotides from the Drosha cutting site in mouse liver and brain (Takada et al. 2006) (FIG. 4H).

FIG. 5A-C. Drosha levels and miRNA profiles during T-cell differentiation. Drosha levels in T-cells measured by qPCR, normalized to β-actin (Chong et al. 2010) (FIG. 5A). Drosha levels in developing mouse brain (GDS3442), normalized to EEF2 (FIG. 5B). Ratio (CD4SP/DN3) of average expression for each miRNA group based on number of mismatches in the 5, 9-12 region (FIG. 5C).

FIG. 6A-C. Changes in gene expression levels during neuronal differentiation. Drosha expression in neuronal differentiation of H1 hESC into Pax6+ neural cells (RNAseq) (FIG. 6A). Number of mismatches in miRNAs with high and low fold change through days 0-6 (multiArray) (FIG. 6B). Number of mismatches in miRNAs with high and low fold change through days 6-12 (multiArray) (FIG. 6C).

FIG. 7A-D. Predicted structures of wild-type and modified hairpins of hsa-mir-145 (FIG. 7A), -137 (FIG. 7B), -9-1 (FIG. 7D) and 200b (FIG. 7C), demonstrating canonical “mismatched” and “rigid” miRNA hairpins. Entropy curves of the nucleotide sequence, starting at the 5′ end, indicate stability changes being local to the changed regions.

FIG. 8A-D. Fold change of over expression levels of wild type and mutated versions of miR-145 (FIG. 8A), -137 (FIG. 8B), -200b (FIG. 8C) and -9 (FIG. 8D) between Drosha knockdown and control HeLa cells, assayed by TaqMan® probes and normalized to RNU66. (n=3). Transfection efficiency was accounted for by SYBRgreen® qPCR of the bleomycin resistance gene in the vector, normalized to GAPDH and subtracted from the ΔCt values from the TaqMan® assays. Final normalization was made to the fold change of over expression for each wt construct. Statistical significance was calculated using a student's t-test, resulting in p-values of <0.01 (mir-145), <0.05 (mir-137), =0.05 (mir-200b).

FIG. 9A-B. in vitro processing of miRNAs using nuclear extract. FIG. 9A. in vitro transcribed miRNAs, processed by 293T cell nuclear extract and visualized on a 10% urea-polyacrylamide gel. Bands corresponding to processed pre-miRNAs are marked in grey, and areas containing pri-miRNAs used for normalization are labeled in black. FIG. 9B. 10/90 minute ratios of quantified pre-miRNA levels normalized to each respective pri-miRNA levels.

FIG. 10. Counting of mismatches in miRNAs in H1 cells with DicerKD and control cells. Mismatches summed for positions counted from the Drosha cutting site for a set of 202 miRNAs split in two equal groups based on fold change (median=0.395) in the Dicer knockdown.

FIG. 11A-B. Drosha protein expression levels in mouse brain and liver. Protein levels of Drosha and β-actin measured by western blots (FIG. 11A). Quantification of Protein levels using triplicates extrapolated from different gels. Fold change=3.2, p<0.05 (FIG. 11B).

FIG. 12. Control mismatch counts for mouse brain and liver. Average expression of miRNAs with different numbers of mismatches in the 1-21 region in mouse liver and brain (Takada et al. 2006).

FIG. 13. Control mismatch ratios in T-cells. Ratio (CD4SP/DN3) of average expression for each miRNA group based on number of mismatches in the 5, 9-12 region.

FIG. 14. Control mismatch counts during neuronal differentiation. Number of mismatches outside the 5, 9-12 region in miRNAs with high and low fold change (multiArray) in neuronal differentiation through days 0-6 and 6-12.

FIG. 15A-B. DroshaKD in HeLa cells, verification of expression levels. Drosha levels measured by qPCR and normalized to GAPDH. 7 biological replicates showed an average 9-fold knock down (log p<−5) (FIG. 15A). Drosha protein expression levels measured by western blotting, normalized to β-actin. 3 biological replicates showed an average 5-fold knockdown (p<0.05) (FIG. 15B).

FIG. 16. Endogenous miRNA levels in DroshaKD and control cells. Endogenous levels for a random selection of miRNAs were measured by TaqMan qPCR, normalized to RNU66. The miRNAs are sorted right to left by increasing number of mismatches in region 9-12 nucleotides from the Drosha cutting site.

FIG. 17A-K. Drosha cutting sites and mis-match positions for: FIG. 17A (hsa-let-7a-1; MI0000060); FIG. 17B (hsa-let-7a-2; MI0000061); FIG. 17C (hsa-let-7a-3; MI0000062); FIG. 17D (hsa-let-7b; MI0000063); FIG. 17E (hsa-let-7c; MI0000064); FIG. 17F (hsa-let-7d; MI0000065); FIG. 17G (hsa-let-7e; MI0000066); FIG. 17H (hsa-let-7f-1; MI0000067); FIG. 17I (hsa-let-7f-2; MI0000068); FIG. 17J (hsa-let-7g; MI0000433) and FIG. 17K (hsa-let-7i; MI0000434).

DETAILED DESCRIPTION

Ribonucleic acid (RNA) is a ubiquitous family of large biological molecules that perform multiple vital roles in the coding, decoding, regulation, and expression of genes. Common types of RNA include double-stranded (dsRNA), double-stranded with a single-stranded overhang, heterogeneous nuclear RNA, messenger RNA (mRNA), micro RNA (miRNA), small nucleolar RNA (snoRNA), ribosomal RNA (rRNA), short interfering RNA (siRNA), small nuclear RNA (snRNA), single-stranded RNA (ssRNA), small hairpin RNA (shRNA), Piwi-interacting RNA (piRNA), transfer RNA (tRNA), long non-coding RNA (lncRNA), long non-coding intergenic RNA (lincRNA) and viral RNA. Particular RNA molecules can fall into more than one RNA type. As used herein, the term “RNA” includes all types of RNA including those listed as the preceding examples and all forms of RNA known to those of ordinary skill in the art. “RNA” can also include any type of nucleic acid polymer that is processed by Drosha or Dicer.

MicroRNAs (miRNA) are a group of short, non-coding RNAs that bind target mRNAs by incomplete complementarity to either inhibit the translation, or reduce the stability of the target mRNA. miRNAs are involved with the onset of various diseases, immunoregulation, neural growth and stem cell renewal and maintenance. Currently 1,872 microRNAs are known to exist in human and many of these are evolutionarily conserved.

miRNAs are transcribed in the nucleus by RNA polymerase II or III as part of a primary microRNA (pri-miRNA). The length of the pri-miRNA is highly variable, ranging from ˜200 up to several thousand nucleotides. The pri-miRNA is cleaved by the Microprocessor, which consists of several components principally Drosha and DGCR8. Drosha and DGCR8 cooperatively bind pri-miRNA, and Drosha cleaves primary transcripts at ˜11 base pairs from the base of the stem-loop and liberates a structure known as the precursor microRNA (pre-miRNA), which is ˜60-70 nucleotides in length and forms a frequently mismatched hairpin structure with a ˜2 nucleotide 3′ overhang. A “stem-loop structure” refers to a nucleic acid having a secondary structure that includes a region of nucleotides which are known or predicted to form a double strand (stem portion) that is linked on one side by a region of predominantly single-stranded nucleotides (loop portion). The terms “hairpin” and “fold-back” structures are also used herein to refer to stem-loop structures. Such structures are well known in the art and the term is used consistently with its known meaning in the art. The actual primary sequence of nucleotides within the stem-loop structure is not critical as long as the secondary structure is present (See FIG. 3A). As is known in the art, the secondary structure does not require exact base-pairing. Thus, the stem may include one or more base mismatches. Alternatively, the base-pairing may be exact, i.e. not include any mismatches.

pre-miRNA is transported from the nucleus to the cytoplasm by Exportin-5 and is subsequently cleaved by the enzyme Dicer with its cofactor trans-activator RNA (tar)-binding protein (TRBP). Dicer binds the 3′-overhang and cleaves the pri-miRNA ˜22nt from the Drosha-cutting site to remove the terminal loop resulting in an imperfect ˜22 nt miRNA/miRNA* duplex. The miRNA enters the RNA-induced silencing complex (RISC), whereas the miRNA* strand is degraded. While this processing mechanism is described in relation to miRNA, it may also apply to all other forms of RNA and nucleic acid polymers processed by Drosha and Dicer.

RNA levels can be regulated in several ways. For example, pri-miRNA transcription is regulated by common transcription factors such as c-Myc. The Microprocessor complex contains several components besides Drosha and DGCR8, such as the DEAD-box helicases p68 and p72, which have been proposed to stabilize the Microprocessor complex. Other components of the Microprocessor include SMAD proteins which have been found to selectively upregulate certain RNAs such as mir-21. The DGCR8 mRNA has stem loop structures that can be cleaved by the Microprocessor, accordingly giving DGCR8 a self regulating mechanism.

The present disclosure shows that decreasing Drosha expression leads to heterogeneous changes in the expression of RNA. The global but non-uniform impact of Drosha knockdown on RNA expression shows that RNAs are not processed by Drosha at equal rates. Non-uniform processing effects indicate that there is some structural relationship between the Microprocessor and the RNAs it cleaves, and any other associated proteins, which could explain the effects of Drosha-knockdown on expression of specific RNAs.

Particular proteins interact with the Microprocessor and/or RNAs to promote or inhibit processing of RNAs. Without being bound by a particular theory, it is possible that protein-based effects explain much of the variation seen in the Drosha knockdown datasets. However, such specific interactions could be considered as part of a complex feed-back mechanism triggered by Drosha-knockdown. In an effort to quantify broad, global mechanisms, which control RNA biogenesis, the genomic origin of 220 miRNAs was first investigated (some miRNAs skip Drosha-processing). Intronic miRNAs were not expressed differently from intergenic miRNAs (FIG. 2). Given that differences in expression were not explained by genomic origin, the secondary structure of RNAs was examined.

Examination of the secondary structure of RNAs was achieved by a counting mechanism and showed that the group of RNAs unaffected or upregulated by Drosha KD had less mismatched bases 5 nt and 9-12 nt from the Drosha cutting site. Additionally, the method of counting resulted in a very consistent measurement of 21 nt, which is consistent with previous reports indicating that Dicer processing of pre-miRNAs with asymmetric mismatches seems to explain the heterogeneity of length observed amongst mature miRNAs, and is also consistent with the idea that Dicer processing utilizes ‘molecular rulers’ which are size invariant. A general mechanism which modulates the Drosha processing step in RNA biogenesis based on differences in secondary structure has not been previously described. However, the structure of DGCR8 suggests that the RNA is bound in a bent position. Mismatches would affect the strain of a bent RNA. Without being bound by a particular theory, the present disclosure suggests that when Drosha levels are limiting, RNAs with fewer mis-matches in positions 5 and 9-12 from the Drosha cutting site are processed more efficiently than RNAs with more mis-matches in positions 5 and 9-12 from the Drosha cutting site.

Drosha cutting sites can be identified by those of ordinary skill in the art. In one embodiment, Drosha cutting sites are derived by comparison of hairpin sequences versus mature 5′ miRNA sequences. The following table provides hairpin sequences associated with mature 5′ miRNA sequences for Drosha cutting site calculation. The beginning of the mature 5′ miRNAs corresponds to the Drosha cutting site.

TABLE 1
Exemplary full hairpin and mature 5′ miRNA sequences, with positions
5 and 9-12,as determined by the counting methods
described herein, shown in bold.
miRNA
name	Full Hairpin Sequence	Mature 5′ Sequence
let-7a-1	UGGGAUGAGGUAGUAGGUUGUAUAGUUUUAGGGUCA	UGAGGUAGUAGGU
	CACCCACCACUGGGAGAUAACUAUACAAUCUACUGUC	UGUAUAGUU (SEQ
	UUUCCUA (SEQ ID NO: 1)	ID NO: 1873)
let-7b	CGGGGUGAGGUAGUAGGUUGUGUGGUUUCAGGGCAG	UGAGGUAGUAGGU
	UGAUGUUGCCCCUCGGAAGAUAACUAUACAACCUACU	UGUGUGGUU (SEQ
	GCCUUCCCUG (SEQ ID NO: 4)	ID NO: 1874)
let-7c	GCAUCCGGGUUGAGGUAGUAGGUUGUAUGGUUUAGA	UGAGGUAGUAGGU
	GUUACACCCUGGGAGUUAACUGUACAACCUUCUAGCU	UGUAUGGUU (SEQ
	UUCCUUGGAGC (SEQ ID NO: 5)	ID NO: 1875)
let-7d	CCUAGGAAGAGGUAGUAGGUUGCAUAGUUUUAGGGC	AGAGGUAGUAGGU
	AGGGAUUUUGCCCACAAGGAGGUAACUAUACGACCUG	UGCAUAGUU (SEQ
	CUGCCUUUCUUAGG (SEQ ID NO: 6)	ID NO: 1876)
let-7e	CCCGGGCUGAGGUAGGAGGUUGUAUAGUUGAGGAGG	UGAGGUAGGAGGU
	ACACCCAAGGAGAUCACUAUACGGCCUCCUAGCUUUC	UGUAUAGUU (SEQ
	CCCAGG (SEQ ID NO: 7)	ID NO: 1877)
let-7f-1	UCAGAGUGAGGUAGUAGAUUGUAUAGUUGUGGGGUA	UGAGGUAGUAGAU
	GUGAUUUUACCCUGUUCAGGAGAUAACUAUACAAUCU	UGUAUAGUU (SEQ
	AUUGCCUUCCCUGA (SEQ ID NO: 8)	ID NO: 1878)
let-7g	AGGCUGAGGUAGUAGUUUGUACAGUUUGAGGGUCUA	UGAGGUAGUAGUU
	UGAUACCACCCGGUACAGGAGAUAACUGUACAGGCCA	UGUACAGUU (SEQ
	CUGCCUUGCCA (SEQ ID NO: 10)	ID NO: 1879)
let-7i	CUGGCUGAGGUAGUAGUUUGUGCUGUUGGUCGGGUU	UGAGGUAGUAGUU
	GUGACAUUGCCCGCUGUGGAGAUAACUGCGCAAGCUA	UGUGCUGUU (SEQ
	CUGCCUUGCUA (SEQ ID NO: 11)	ID NO: 1880)
miR-21	UGUCGGGUAGCUUAUCAGACUGAUGUUGACUGUUGA	UAGCUUAUCAGAC
	AUCUCAUGGCAACACCAGUCGAUGGGCUGUCUGACA	UGAUGUUGA (SEQ
	(SEQ ID NO: 130)	ID NO: 2021)
miR-126	CGCUGGCGACGGGACAUUAUUACUUUUGGUACGCGC	CAUUAUUACUUUU
	UGUGACACUUCAAACUCGUACCGUGAGUAAUAAUGCG	GGUACGCG (SEQ
	CCGUCCACGGCA (SEQ ID NO: 35)	ID NO: 1914)
miR-152	UGUCCCCCCCGGCCCAGGUUCUGUGAUACACUCCGA	AGGUUCUGUGAUA
	CUCGGGCUCUGGAGCAGUCAGUGCAUGACAGAACUU	CACUCCGACU
	GGGCCCGGAAGGACC (SEQ ID NO: 72)	(SEQ ID NO: 1960)

The calculation as described in the preceding table can be performed based on the hairpin and mature 5′ sequences of the sequences provided in this disclosure's sequence listing. The following combinations of sequences provide related hairpin and mature 5′ sequences.

	Name	Hairpin	Mature 5′
	let-7a-1	SEQ ID NO: 1	SEQ ID
			NO: 1873
	let-7a-2	SEQ ID NO: 2	SEQ ID
			NO: 1873
	let-7a-3	SEQ ID NO: 3	SEQ ID
			NO: 1873
	let-7b	SEQ ID NO: 4	SEQ ID
			NO: 1874
	let-7c	SEQ ID NO: 5	SEQ ID
			NO: 1875
	let-7d	SEQ ID NO: 6	SEQ ID
			NO: 1876
	let-7e	SEQ ID NO: 7	SEQ ID
			NO: 1877
	let-7f-1	SEQ ID NO: 8	SEQ ID
			NO: 1878
	let-7f-2	SEQ ID NO: 9	SEQ ID
			NO: 1878
	let-7g	SEQ ID	SEQ ID
		NO: 10	NO: 1879
	let-7i	SEQ ID	SEQ ID
		NO: 11	NO: 1880
	mir-7-3	SEQ ID	SEQ ID
		NO: 279	NO: 2708
	mir-7-2	SEQ ID	SEQ ID
		NO: 278	NO: 2708
	mir-7-1	SEQ ID	SEQ ID
		NO: 277	NO: 2708
	mir-9-3	SEQ ID	SEQ ID
		NO: 286	NO: 2739
	mir-9-2	SEQ ID	SEQ ID
		NO: 281	NO: 2739
	mir-9-1	SEQ ID	SEQ ID
		NO: 280	NO: 2739
	mir-10a	SEQ ID	SEQ ID
		NO: 24	NO: 1887
	mir-10b	SEQ ID	SEQ ID
		NO: 25	NO: 1888
	mir-15a	SEQ ID	SEQ ID
		NO: 77	NO: 1965
	mir-15b	SEQ ID	SEQ ID
		NO: 78	NO: 1966
	mir-16-1	SEQ ID	SEQ ID
		NO: 79	NO: 1967
	mir-16-2	SEQ ID	SEQ ID
		NO: 80	NO: 1967
	mir-17	SEQ ID	SEQ ID
		NO: 81	NO: 1968
	mir-18a	SEQ ID	SEQ ID
		NO: 95	NO: 1979
	mir-18b	SEQ ID	SEQ ID
		NO: 96	NO: 1980
	mir-19a	SEQ ID	SEQ ID
		NO: 114	NO: 1999
	mir-19b-1	SEQ ID	SEQ ID
		NO: 115	NO: 2000
	mir-19b-2	SEQ ID	SEQ ID
		NO: 116	NO: 2001
	mir-20a	SEQ ID	SEQ ID
		NO: 128	NO: 2011
	mir-20b	SEQ ID	SEQ ID
		NO: 129	NO: 2012
	mir-21	SEQ ID	SEQ ID
		NO: 130	NO: 2021
	mir-22	SEQ ID	SEQ ID
		NO: 144	NO: 2031
	mir-23a	SEQ ID	SEQ ID
		NO: 149	NO: 2035
	mir-23b	SEQ ID	SEQ ID
		NO: 150	NO: 2036
	mir-24-2	SEQ ID	SEQ ID
		NO: 153	NO: 2038
	mir-24-1	SEQ ID	SEQ ID
		NO: 152	NO: 2037
	mir-25	SEQ ID	SEQ ID
		NO: 154	NO: 2040
	mir-26a-1	SEQ ID	SEQ ID
		NO: 155	NO: 2043
	mir-26a-2	SEQ ID	SEQ ID
		NO: 156	NO: 2043
	mir-26b	SEQ ID	SEQ ID
		NO: 157	NO: 2044
	mir-27a	SEQ ID	SEQ ID
		NO: 158	NO: 2045
	mir-27b	SEQ ID	SEQ ID
		NO: 159	NO: 2046
	mir-28	SEQ ID	SEQ ID
		NO: 160	NO: 2047
	mir-29a	SEQ ID	SEQ ID
		NO: 165	NO: 2050
	mir-29b-1	SEQ ID	SEQ ID
		NO: 166	NO: 2051
	mir-29b-2	SEQ ID	SEQ ID
		NO: 167	NO: 2052
	mir-29c	SEQ ID	SEQ ID
		NO: 168	NO: 2053
	mir-30a	SEQ ID	SEQ ID
		NO: 178	NO: 2062
	mir-30b	SEQ ID	SEQ ID
		NO: 179	NO: 2063
	mir-30c-1	SEQ ID	SEQ ID
		NO: 180	NO: 2064
	mir-30c-2	SEQ ID	SEQ ID
		NO: 181	NO: 2064
	mir-30d	SEQ ID	SEQ ID
		NO: 182	NO: 2065
	mir-30e	SEQ ID	SEQ ID
		NO: 183	NO: 2066
	mir-31	SEQ ID	SEQ ID
		NO: 184	NO: 2086
	mir-32	SEQ ID	SEQ ID
		NO: 185	NO: 2104
	mir-33a	SEQ ID	SEQ ID
		NO: 208	NO: 2113
	mir-33b	SEQ ID	SEQ ID
		NO: 209	NO: 2114
	mir-34a	SEQ ID	SEQ ID
		NO: 214	NO: 2118
	mir-34b	SEQ ID	SEQ ID
		NO: 215	NO: 2119
	mir-34c	SEQ ID	SEQ ID
		NO: 216	NO: 2120
	mir-92a-1	SEQ ID	SEQ ID
		NO: 282	NO: 2731
	mir-92a-2	SEQ ID	SEQ ID
		NO: 283	NO: 2732
	mir-92b	SEQ ID	SEQ ID
		NO: 284	NO: 2733
	mir-93	SEQ ID	SEQ ID
		NO: 285	NO: 2734
	mir-95	SEQ ID	SEQ ID
		NO: 287	NO: 2738
	mir-96	SEQ ID	SEQ ID
		NO: 288	NO: 2740
	mir-98	SEQ ID	SEQ ID
		NO: 289	NO: 2741
	mir-99a	SEQ ID	SEQ ID
		NO: 290	NO: 2742
	mir-99b	SEQ ID	SEQ ID
		NO: 291	NO: 2743
	mir-100	SEQ ID	SEQ ID
		NO: 12	NO: 1881
	mir-101-2	SEQ ID	SEQ ID
		NO: 14	NO: 1882
	mir-101-1	SEQ ID	SEQ ID
		NO: 13	NO: 1882
	mir-103a-2	SEQ ID	SEQ ID
		NO: 16	NO: 1883
	mir-105-2	SEQ ID	SEQ ID
		NO: 20	NO: 1884
	mir-105-1	SEQ ID	SEQ ID
		NO: 19	NO: 1884
	mir-106a	SEQ ID	SEQ ID
		NO: 21	NO: 1885
	mir-106b	SEQ ID	SEQ ID
		NO: 22	NO: 1886
	mir-122	SEQ ID	SEQ ID
		NO: 28	NO: 1896
	mir-124-3	SEQ ID	SEQ ID
		NO: 31	NO: 1906
	mir-124-2	SEQ ID	SEQ ID
		NO: 30	NO: 1906
	mir-124-1	SEQ ID	SEQ ID
		NO: 29	NO: 1906
	mir-125a	SEQ ID	SEQ ID
		NO: 32	NO: 1912
	mir-125b-1	SEQ ID	SEQ ID
		NO: 33	NO: 1913
	mir-125b-2	SEQ ID	SEQ ID
		NO: 34	NO: 1913
	mir-126	SEQ ID	SEQ ID
		NO: 35	NO: 1914
	mir-127	SEQ ID	SEQ ID
		NO: 36	NO: 1919
	mir-128-1	SEQ ID	SEQ ID
		NO: 37	NO: 1921
	mir-128-2	SEQ ID	SEQ ID
		NO: 38	NO: 1922
	mir-129-2	SEQ ID	SEQ ID
		NO: 40	NO: 1928
	mir-129-1	SEQ ID	SEQ ID
		NO: 39	NO: 1928
	mir-130a	SEQ ID	SEQ ID
		NO: 41	NO: 1935
	mir-130b	SEQ ID	SEQ ID
		NO: 42	NO: 1936
	mir-132	SEQ ID	SEQ ID
		NO: 43	NO: 1937
	mir-133a-1	SEQ ID	SEQ ID
		NO: 44	NO: 1938
	mir-133a-2	SEQ ID	SEQ ID
		NO: 45	NO: 1938
	mir-134	SEQ ID	SEQ ID
		NO: 47	NO: 1940
	mir-135a-1	SEQ ID	SEQ ID
		NO: 48	NO: 1941
	mir-135a-2	SEQ ID	SEQ ID
		NO: 49	NO: 1941
	mir-135b	SEQ ID	SEQ ID
		NO: 50	NO: 1942
	mir-136	SEQ ID	SEQ ID
		NO: 51	NO: 1943
	mir-138-2	SEQ ID	SEQ ID
		NO: 54	NO: 1944
	mir-138-1	SEQ ID	SEQ ID
		NO: 53	NO: 1944
	mir-139	SEQ ID	SEQ ID
		NO: 55	NO: 1945
	mir-140	SEQ ID	SEQ ID
		NO: 56	NO: 1946
	mir-141	SEQ ID	SEQ ID
		NO: 57	NO: 1947
	mir-142	SEQ ID	SEQ ID
		NO: 58	NO: 1948
	mir-143	SEQ ID	SEQ ID
		NO: 59	NO: 1949
	mir-144	SEQ ID	SEQ ID
		NO: 60	NO: 1950
	mir-145	SEQ ID	SEQ ID
		NO: 61	NO: 1951
	mir-146a	SEQ ID	SEQ ID
		NO: 62	NO: 1953
	mir-146b	SEQ ID	SEQ ID
		NO: 63	NO: 1954
	mir-148a	SEQ ID	SEQ ID
		NO: 66	NO: 1955
	mir-148b	SEQ ID	SEQ ID
		NO: 67	NO: 1956
	mir-149	SEQ ID	SEQ ID
		NO: 68	NO: 1957
	mir-150	SEQ ID	SEQ ID
		NO: 69	NO: 1958
	mir-151a	SEQ ID	SEQ ID
		NO: 70	NO: 1959
	mir-152	SEQ ID	SEQ ID
		NO: 72	NO: 1960
	mir-153-2	SEQ ID	SEQ ID
		NO: 74	NO: 1961
	mir-153-1	SEQ ID	SEQ ID
		NO: 73	NO: 1961
	mir-154	SEQ ID	SEQ ID
		NO: 75	NO: 1963
	mir-155	SEQ ID	SEQ ID
		NO: 76	NO: 1964
	mir-181a-1	SEQ ID	SEQ ID
		NO: 82	NO: 1969
	mir-181a-2	SEQ ID	SEQ ID
		NO: 83	NO: 1969
	mir-181b-1	SEQ ID	SEQ ID
		NO: 84	NO: 1970
	mir-181b-2	SEQ ID	SEQ ID
		NO: 85	NO: 1970
	mir-181c	SEQ ID	SEQ ID
		NO: 86	NO: 1971
	mir-181d	SEQ ID	SEQ ID
		NO: 87	NO: 1972
	mir-182	SEQ ID	SEQ ID
		NO: 88	NO: 1973
	mir-183	SEQ ID	SEQ ID
		NO: 89	NO: 1974
	mir-185	SEQ ID	SEQ ID
		NO: 91	NO: 1975
	mir-186	SEQ ID	SEQ ID
		NO: 92	NO: 1976
	mir-187	SEQ ID	SEQ ID
		NO: 93	NO: 1977
	mir-188	SEQ ID	SEQ ID
		NO: 94	NO: 1978
	mir-190a	SEQ ID	SEQ ID
		NO: 97	NO: 1983
	mir-191	SEQ ID	SEQ ID
		NO: 99	NO: 1988
	mir-192	SEQ ID	SEQ ID
		NO: 100	NO: 1989
	mir-193a	SEQ ID	SEQ ID
		NO: 101	NO: 1990
	mir-193b	SEQ ID	SEQ ID
		NO: 102	NO: 1991
	mir-194-2	SEQ ID	SEQ ID
		NO: 104	NO: 1992
	mir-194-1	SEQ ID	SEQ ID
		NO: 103	NO: 1992
	mir-195	SEQ ID	SEQ ID
		NO: 105	NO: 1993
	mir-196a-1	SEQ ID	SEQ ID
		NO: 106	NO: 1994
	mir-196a-2	SEQ ID	SEQ ID
		NO: 107	NO: 1994
	mir-196b	SEQ ID	SEQ ID
		NO: 108	NO: 1995
	mir-197	SEQ ID	SEQ ID
		NO: 109	NO: 1996
	mir-199a-1	SEQ ID	SEQ ID
		NO: 111	NO: 1997
	mir-199a-2	SEQ ID	SEQ ID
		NO: 112	NO: 1997
	mir-199b	SEQ ID	SEQ ID
		NO: 113	NO: 1998
	mir-200a	SEQ ID	SEQ ID
		NO: 117	NO: 2002
	mir-200b	SEQ ID	SEQ ID
		NO: 118	NO: 2003
	mir-200c	SEQ ID	SEQ ID
		NO: 119	NO: 2004
	mir-202	SEQ ID	SEQ ID
		NO: 120	NO: 2005
	mir-203b	SEQ ID	SEQ ID
		NO: 122	NO: 2006
	mir-204	SEQ ID	SEQ ID
		NO: 123	NO: 2007
	mir-205	SEQ ID	SEQ ID
		NO: 124	NO: 2008
	mir-208a	SEQ ID	SEQ ID
		NO: 126	NO: 2009
	mir-208b	SEQ ID	SEQ ID
		NO: 127	NO: 2010
	mir-210	SEQ ID	SEQ ID
		NO: 131	NO: 2013
	mir-211	SEQ ID	SEQ ID
		NO: 132	NO: 2016
	mir-212	SEQ ID	SEQ ID
		NO: 133	NO: 2018
	mir-214	SEQ ID	SEQ ID
		NO: 134	NO: 2019
	mir-215	SEQ ID	SEQ ID
		NO: 135	NO: 2020
	mir-216a	SEQ ID	SEQ ID
		NO: 136	NO: 2022
	mir-216b	SEQ ID	SEQ ID
		NO: 137	NO: 2023
	mir-218-2	SEQ ID	SEQ ID
		NO: 140	NO: 2024
	mir-218-1	SEQ ID	SEQ ID
		NO: 139	NO: 2024
	mir-219a-1	SEQ ID	SEQ ID
		NO: 141	NO: 2025
	mir-219a-2	SEQ ID	SEQ ID
		NO: 142	NO: 2025
	mir-219b	SEQ ID	SEQ ID
		NO: 143	NO: 2026
	mir-221	SEQ ID	SEQ ID
		NO: 145	NO: 2027
	mir-222	SEQ ID	SEQ ID
		NO: 146	NO: 2028
	mir-223	SEQ ID	SEQ ID
		NO: 147	NO: 2029
	mir-224	SEQ ID	SEQ ID
		NO: 148	NO: 2030
	mir-296	SEQ ID	SEQ ID
		NO: 161	NO: 2048
	mir-299	SEQ ID	SEQ ID
		NO: 164	NO: 2049
	mir-301a	SEQ ID	SEQ ID
		NO: 170	NO: 2054
	mir-302a	SEQ ID	SEQ ID
		NO: 172	NO: 2055
	mir-302b	SEQ ID	SEQ ID
		NO: 173	NO: 2056
	mir-302c	SEQ ID	SEQ ID
		NO: 174	NO: 2057
	mir-302d	SEQ ID	SEQ ID
		NO: 175	NO: 2058
	mir-323a	SEQ ID	SEQ ID
		NO: 194	NO: 2101
	mir-323b	SEQ ID	SEQ ID
		NO: 195	NO: 2102
	mir-324	SEQ ID	SEQ ID
		NO: 196	NO: 2103
	mir-328	SEQ ID	SEQ ID
		NO: 199	NO: 2105
	mir-329-2	SEQ ID	SEQ ID
		NO: 201	NO: 2106
	mir-329-1	SEQ ID	SEQ ID
		NO: 200	NO: 2106
	mir-330	SEQ ID	SEQ ID
		NO: 202	NO: 2107
	mir-331	SEQ ID	SEQ ID
		NO: 203	NO: 2108
	mir-335	SEQ ID	SEQ ID
		NO: 204	NO: 2109
	mir-337	SEQ ID	SEQ ID
		NO: 205	NO: 2110
	mir-338	SEQ ID	SEQ ID
		NO: 206	NO: 2111
	mir-339	SEQ ID	SEQ ID
		NO: 207	NO: 2112
	mir-340	SEQ ID	SEQ ID
		NO: 210	NO: 2115
	mir-342	SEQ ID	SEQ ID
		NO: 211	NO: 2116
	mir-345	SEQ ID	SEQ ID
		NO: 212	NO: 2117
	mir-361	SEQ ID	SEQ ID
		NO: 217	NO: 2128
	mir-362	SEQ ID	SEQ ID
		NO: 218	NO: 2135
	mir-363	SEQ ID	SEQ ID
		NO: 219	NO: 2136
	mir-365a	SEQ ID	SEQ ID
		NO: 220	NO: 2137
	mir-365b	SEQ ID	SEQ ID
		NO: 221	NO: 2138
	mir-367	SEQ ID	SEQ ID
		NO: 222	NO: 2143
	mir-369	SEQ ID	SEQ ID
		NO: 223	NO: 2155
	mir-370	SEQ ID	SEQ ID
		NO: 224	NO: 2156
	mir-371a	SEQ ID	SEQ ID
		NO: 225	NO: 2157
	mir-371b	SEQ ID	SEQ ID
		NO: 226	NO: 2158
	mir-372	SEQ ID	SEQ ID
		NO: 227	NO: 2159
	mir-373	SEQ ID	SEQ ID
		NO: 228	NO: 2160
	mir-374a	SEQ ID	SEQ ID
		NO: 229	NO: 2161
	mir-374b	SEQ ID	SEQ ID
		NO: 230	NO: 2162
	mir-374c	SEQ ID	SEQ ID
		NO: 231	NO: 2163
	mir-376a-1	SEQ ID	SEQ ID
		NO: 233	NO: 2165
	mir-376a-2	SEQ ID	SEQ ID
		NO: 234	NO: 2164
	mir-376b	SEQ ID	SEQ ID
		NO: 235	NO: 2166
	mir-376c	SEQ ID	SEQ ID
		NO: 236	NO: 2167
	mir-377	SEQ ID	SEQ ID
		NO: 237	NO: 2168
	mir-378a	SEQ ID	SEQ ID
		NO: 238	NO: 2169
	mir-379	SEQ ID	SEQ ID
		NO: 249	NO: 2170
	mir-380	SEQ ID	SEQ ID
		NO: 250	NO: 2171
	mir-381	SEQ ID	SEQ ID
		NO: 251	NO: 2172
	mir-382	SEQ ID	SEQ ID
		NO: 252	NO: 2173
	mir-383	SEQ ID	SEQ ID
		NO: 253	NO: 2174
	mir-409	SEQ ID	SEQ ID
		NO: 255	NO: 2185
	mir-410	SEQ ID	SEQ ID
		NO: 256	NO: 2186
	mir-411	SEQ ID	SEQ ID
		NO: 257	NO: 2187
	mir-412	SEQ ID	SEQ ID
		NO: 258	NO: 2188
	mir-423	SEQ ID	SEQ ID
		NO: 261	NO: 2189
	mir-424	SEQ ID	SEQ ID
		NO: 262	NO: 2190
	mir-425	SEQ ID	SEQ ID
		NO: 263	NO: 2191
	mir-431	SEQ ID	SEQ ID
		NO: 265	NO: 2192
	mir-432	SEQ ID	SEQ ID
		NO: 266	NO: 2193
	mir-433	SEQ ID	SEQ ID
		NO: 267	NO: 2194
	mir-449b	SEQ ID	SEQ ID
		NO: 270	NO: 2203
	mir-449c	SEQ ID	SEQ ID
		NO: 271	NO: 2204
	mir-450a-1	SEQ ID	SEQ ID
		NO: 272	NO: 2205
	mir-450a-2	SEQ ID	SEQ ID
		NO: 273	NO: 2205
	mir-450b	SEQ ID	SEQ ID
		NO: 274	NO: 2206
	mir-452	SEQ ID	SEQ ID
		NO: 292	NO: 2211
	mir-454	SEQ ID	SEQ ID
		NO: 293	NO: 2214
	mir-455	SEQ ID	SEQ ID
		NO: 294	NO: 2215
	mir-483	SEQ ID	SEQ ID
		NO: 296	NO: 2321
	mir-485	SEQ ID	SEQ ID
		NO: 298	NO: 2322
	mir-486-2	SEQ ID	SEQ ID
		NO: 300	NO: 2323
	mir-486	SEQ ID	SEQ ID
		NO: 299	NO: 2323
	mir-487a	SEQ ID	SEQ ID
		NO: 301	NO: 2324
	mir-487b	SEQ ID	SEQ ID
		NO: 302	NO: 2325
	mir-488	SEQ ID	SEQ ID
		NO: 303	NO: 2326
	mir-489	SEQ ID	SEQ ID
		NO: 304	NO: 2327
	mir-490	SEQ ID	SEQ ID
		NO: 305	NO: 2328
	mir-491	SEQ ID	SEQ ID
		NO: 306	NO: 2329
	mir-493	SEQ ID	SEQ ID
		NO: 308	NO: 2330
	mir-494	SEQ ID	SEQ ID
		NO: 309	NO: 2331
	mir-495	SEQ ID	SEQ ID
		NO: 310	NO: 2332
	mir-497	SEQ ID	SEQ ID
		NO: 312	NO: 2333
	mir-499a	SEQ ID	SEQ ID
		NO: 314	NO: 2335
	mir-499b	SEQ ID	SEQ ID
		NO: 315	NO: 2336
	mir-500a	SEQ ID	SEQ ID
		NO: 316	NO: 2346
	mir-500b	SEQ ID	SEQ ID
		NO: 317	NO: 2347
	mir-501	SEQ ID	SEQ ID
		NO: 318	NO: 2350
	mir-502	SEQ ID	SEQ ID
		NO: 319	NO: 2351
	mir-503	SEQ ID	SEQ ID
		NO: 320	NO: 2352
	mir-504	SEQ ID	SEQ ID
		NO: 321	NO: 2353
	mir-505	SEQ ID	SEQ ID
		NO: 322	NO: 2354
	mir-506	SEQ ID	SEQ ID
		NO: 323	NO: 2355
	mir-508	SEQ ID	SEQ ID
		NO: 325	NO: 2356
	mir-509-3	SEQ ID	SEQ ID
		NO: 328	NO: 2359
	mir-509-2	SEQ ID	SEQ ID
		NO: 327	NO: 2360
	mir-509-1	SEQ ID	SEQ ID
		NO: 326	NO: 2360
	mir-510	SEQ ID	SEQ ID
		NO: 329	NO: 2361
	mir-511	SEQ ID	SEQ ID
		NO: 330	NO: 2362
	mir-512-2	SEQ ID	SEQ ID
		NO: 332	NO: 2363
	mir-512-1	SEQ ID	SEQ ID
		NO: 331	NO: 2363
	mir-513a-1	SEQ ID	SEQ ID
		NO: 333	NO: 2364
	mir-513a-2	SEQ ID	SEQ ID
		NO: 334	NO: 2364
	mir-513b	SEQ ID	SEQ ID
		NO: 335	NO: 2365
	mir-513c	SEQ ID	SEQ ID
		NO: 336	NO: 2366
	mir-514a-1	SEQ ID	SEQ ID
		NO: 337	NO: 2367
	mir-514a-2	SEQ ID	SEQ ID
		NO: 338	NO: 2367
	mir-514a-3	SEQ ID	SEQ ID
		NO: 339	NO: 2367
	mir-514b	SEQ ID	SEQ ID
		NO: 340	NO: 2368
	mir-515-2	SEQ ID	SEQ ID
		NO: 342	NO: 2369
	mir-515-1	SEQ ID	SEQ ID
		NO: 341	NO: 2369
	mir-516a-1	SEQ ID	SEQ ID
		NO: 343	NO: 2370
	mir-516a-2	SEQ ID	SEQ ID
		NO: 344	NO: 2370
	mir-516b-1	SEQ ID	SEQ ID
		NO: 345	NO: 2371
	mir-516b-2	SEQ ID	SEQ ID
		NO: 346	NO: 2371
	mir-517a	SEQ ID	SEQ ID
		NO: 347	NO: 2372
	mir-517b	SEQ ID	SEQ ID
		NO: 348	NO: 2372
	mir-517c	SEQ ID	SEQ ID
		NO: 349	NO: 2372
	mir-518a-1	SEQ ID	SEQ ID
		NO: 350	NO: 2375
	mir-518a-2	SEQ ID	SEQ ID
		NO: 351	NO: 2375
	mir-518c	SEQ ID	SEQ ID
		NO: 353	NO: 2376
	mir-518d	SEQ ID	SEQ ID
		NO: 354	NO: 2377
	mir-518e	SEQ ID	SEQ ID
		NO: 355	NO: 2378
	mir-518f	SEQ ID	SEQ ID
		NO: 356	NO: 2379
	mir-519a-1	SEQ ID	SEQ ID
		NO: 357	NO: 2383
	mir-519a-2	SEQ ID	SEQ ID
		NO: 358	NO: 2383
	mir-519b	SEQ ID	SEQ ID
		NO: 359	NO: 2384
	mir-519c	SEQ ID	SEQ ID
		NO: 360	NO: 2385
	mir-519d	SEQ ID	SEQ ID
		NO: 361	NO: 2386
	mir-519e	SEQ ID	SEQ ID
		NO: 362	NO: 2387
	mir-520a	SEQ ID	SEQ ID
		NO: 363	NO: 2388
	mir-520c	SEQ ID	SEQ ID
		NO: 365	NO: 2389
	mir-520d	SEQ ID	SEQ ID
		NO: 366	NO: 2390
	mir-520f	SEQ ID	SEQ ID
		NO: 368	NO: 2391
	mir-520g	SEQ ID	SEQ ID
		NO: 369	NO: 2392
	mir-522	SEQ ID	SEQ ID
		NO: 373	NO: 2393
	mir-523	SEQ ID	SEQ ID
		NO: 374	NO: 2394
	mir-524	SEQ ID	SEQ ID
		NO: 375	NO: 2395
	mir-525	SEQ ID	SEQ ID
		NO: 376	NO: 2396
	mir-526b	SEQ ID	SEQ ID
		NO: 379	NO: 2397
	mir-532	SEQ ID	SEQ ID
		NO: 381	NO: 2398
	mir-539	SEQ ID	SEQ ID
		NO: 382	NO: 2399
	mir-541	SEQ ID	SEQ ID
		NO: 383	NO: 2400
	mir-542	SEQ ID	SEQ ID
		NO: 384	NO: 2401
	mir-545	SEQ ID	SEQ ID
		NO: 388	NO: 2402
	mir-548a-1	SEQ ID	SEQ ID
		NO: 389	NO: 2403
	mir-548a-2	SEQ ID	SEQ ID
		NO: 390	NO: 2403
	mir-548a-3	SEQ ID	SEQ ID
		NO: 391	NO: 2403
	mir-548ah	SEQ ID	SEQ ID
		NO: 401	NO: 2404
	mir-548aj-1	SEQ ID	SEQ ID
		NO: 403	NO: 2405
	mir-548aj-2	SEQ ID	SEQ ID
		NO: 404	NO: 2405
	mir-548am	SEQ ID	SEQ ID
		NO: 407	NO: 2406
	mir-548ao	SEQ ID	SEQ ID
		NO: 409	NO: 2407
	mir-548ap	SEQ ID	SEQ ID
		NO: 410	NO: 2408
	mir-548aq	SEQ ID	SEQ ID
		NO: 411	NO: 2409
	mir-548ar	SEQ ID	SEQ ID
		NO: 412	NO: 2410
	mir-548as	SEQ ID	SEQ ID
		NO: 413	NO: 2411
	mir-548at	SEQ ID	SEQ ID
		NO: 414	NO: 2412
	mir-548au	SEQ ID	SEQ ID
		NO: 415	NO: 2413
	mir-548av	SEQ ID	SEQ ID
		NO: 416	NO: 2414
	mir-548ay	SEQ ID	SEQ ID
		NO: 419	NO: 2415
	mir-548az	SEQ ID	SEQ ID
		NO: 420	NO: 2416
	mir-548b	SEQ ID	SEQ ID
		NO: 421	NO: 2417
	mir-548ba	SEQ ID	SEQ ID
		NO: 422	NO: 2417
	mir-548c	SEQ ID	SEQ ID
		NO: 423	NO: 2418
	mir-548d-1	SEQ ID	SEQ ID
		NO: 424	NO: 2419
	mir-548d-2	SEQ ID	SEQ ID
		NO: 425	NO: 2419
	mir-548e	SEQ ID	SEQ ID
		NO: 426	NO: 2420
	mir-548f-1	SEQ ID	SEQ ID
		NO: 427	NO: 2421
	mir-548f-2	SEQ ID	SEQ ID
		NO: 428	NO: 2421
	mir-548f-3	SEQ ID	SEQ ID
		NO: 429	NO: 2421
	mir-548f-4	SEQ ID	SEQ ID
		NO: 430	NO: 2421
	mir-548f-5	SEQ ID	SEQ ID
		NO: 431	NO: 2421
	mir-548g	SEQ ID	SEQ ID
		NO: 432	NO: 2422
	mir-548h-1	SEQ ID	SEQ ID
		NO: 433	NO: 2423
	mir-548h-2	SEQ ID	SEQ ID
		NO: 434	NO: 2423
	mir-548h-3	SEQ ID	SEQ ID
		NO: 435	NO: 2423
	mir-548h-4	SEQ ID	SEQ ID
		NO: 436	NO: 2423
	mir-548h-5	SEQ ID	SEQ ID
		NO: 437	NO: 2423
	mir-548j	SEQ ID	SEQ ID
		NO: 442	NO: 2424
	mir-548o	SEQ ID	SEQ ID
		NO: 447	NO: 2425
	mir-548o-2	SEQ ID	SEQ ID
		NO: 448	NO: 2425
	mir-548t	SEQ ID	SEQ ID
		NO: 452	NO: 2426
	mir-548x	SEQ ID	SEQ ID
		NO: 456	NO: 2427
	mir-548x-2	SEQ ID	SEQ ID
		NO: 457	NO: 2427
	mir-550a-1	SEQ ID	SEQ ID
		NO: 461	NO: 2429
	mir-550a-2	SEQ ID	SEQ ID
		NO: 462	NO: 2429
	mir-550a-3	SEQ ID	SEQ ID
		NO: 463	NO: 2428
	mir-550b-2	SEQ ID	SEQ ID
		NO: 465	NO: 2430
	mir-551b	SEQ ID	SEQ ID
		NO: 467	NO: 2431
	mir-552	SEQ ID	SEQ ID
		NO: 468	NO: 2432
	mir-556	SEQ ID	SEQ ID
		NO: 472	NO: 2433
	mir-561	SEQ ID	SEQ ID
		NO: 476	NO: 2448
	mir-570	SEQ ID	SEQ ID
		NO: 484	NO: 2450
	mir-574	SEQ ID	SEQ ID
		NO: 488	NO: 2451
	mir-576	SEQ ID	SEQ ID
		NO: 490	NO: 2452
	mir-579	SEQ ID	SEQ ID
		NO: 493	NO: 2453
	mir-580	SEQ ID	SEQ ID
		NO: 494	NO: 2454
	mir-582	SEQ ID	SEQ ID
		NO: 496	NO: 2455
	mir-584	SEQ ID	SEQ ID
		NO: 498	NO: 2456
	mir-585	SEQ ID	SEQ ID
		NO: 499	NO: 2457
	mir-589	SEQ ID	SEQ ID
		NO: 503	NO: 2458
	mir-590	SEQ ID	SEQ ID
		NO: 504	NO: 2459
	mir-593	SEQ ID	SEQ ID
		NO: 507	NO: 2460
	mir-597	SEQ ID	SEQ ID
		NO: 510	NO: 2461
	mir-598	SEQ ID	SEQ ID
		NO: 511	NO: 2462
	mir-605	SEQ ID	SEQ ID
		NO: 518	NO: 2463
	mir-615	SEQ ID	SEQ ID
		NO: 528	NO: 2464
	mir-616	SEQ ID	SEQ ID
		NO: 529	NO: 2465
	mir-619	SEQ ID	SEQ ID
		NO: 532	NO: 2466
	mir-624	SEQ ID	SEQ ID
		NO: 537	NO: 2467
	mir-625	SEQ ID	SEQ ID
		NO: 538	NO: 2468
	mir-627	SEQ ID	SEQ ID
		NO: 540	NO: 2469
	mir-628	SEQ ID	SEQ ID
		NO: 541	NO: 2470
	mir-629	SEQ ID	SEQ ID
		NO: 542	NO: 2471
	mir-642a	SEQ ID	SEQ ID
		NO: 555	NO: 2472
	mir-642b	SEQ ID	SEQ ID
		NO: 556	NO: 2473
	mir-651	SEQ ID	SEQ ID
		NO: 565	NO: 2492
	mir-652	SEQ ID	SEQ ID
		NO: 566	NO: 2494
	mir-653	SEQ ID	SEQ ID
		NO: 567	NO: 2495
	mir-654	SEQ ID	SEQ ID
		NO: 568	NO: 2496
	mir-655	SEQ ID	SEQ ID
		NO: 569	NO: 2497
	mir-656	SEQ ID	SEQ ID
		NO: 570	NO: 2498
	mir-659	SEQ ID	SEQ ID
		NO: 573	NO: 2499
	mir-660	SEQ ID	SEQ ID
		NO: 574	NO: 2500
	mir-664a	SEQ ID	SEQ ID
		NO: 579	NO: 2501
	mir-664b	SEQ ID	SEQ ID
		NO: 580	NO: 2502
	mir-668	SEQ ID	SEQ ID
		NO: 582	NO: 2503
	mir-670	SEQ ID	SEQ ID
		NO: 583	NO: 2504
	mir-671	SEQ ID	SEQ ID
		NO: 584	NO: 2506
	mir-675	SEQ ID	SEQ ID
		NO: 585	NO: 2544
	mir-676	SEQ ID	SEQ ID
		NO: 586	NO: 2555
	mir-708	SEQ ID	SEQ ID
		NO: 587	NO: 2684
	mir-744	SEQ ID	SEQ ID
		NO: 590	NO: 2706
	mir-758	SEQ ID	SEQ ID
		NO: 591	NO: 2707
	mir-766	SEQ ID	SEQ ID
		NO: 598	NO: 2709
	mir-767	SEQ ID	SEQ ID
		NO: 599	NO: 2710
	mir-769	SEQ ID	SEQ ID
		NO: 600	NO: 2711
	mir-770	SEQ ID	SEQ ID
		NO: 601	NO: 2712
	mir-873	SEQ ID	SEQ ID
		NO: 603	NO: 2720
	mir-874	SEQ ID	SEQ ID
		NO: 604	NO: 2721
	mir-875	SEQ ID	SEQ ID
		NO: 605	NO: 2722
	mir-876	SEQ ID	SEQ ID
		NO: 606	NO: 2723
	mir-877	SEQ ID	SEQ ID
		NO: 607	NO: 2724
	mir-885	SEQ ID	SEQ ID
		NO: 608	NO: 2725
	mir-887	SEQ ID	SEQ ID
		NO: 609	NO: 2726
	mir-888	SEQ ID	SEQ ID
		NO: 610	NO: 2727
	mir-889	SEQ ID	SEQ ID
		NO: 611	NO: 2728
	mir-891a	SEQ ID	SEQ ID
		NO: 613	NO: 2729
	mir-892c	SEQ ID	SEQ ID
		NO: 617	NO: 2730
	mir-937	SEQ ID	SEQ ID
		NO: 626	NO: 2735
	mir-939	SEQ ID	SEQ ID
		NO: 628	NO: 2736
	mir-942	SEQ ID	SEQ ID
		NO: 634	NO: 2737
	mir-1178	SEQ ID	SEQ ID
		NO: 637	NO: 1889
	mir-1180	SEQ ID	SEQ ID
		NO: 639	NO: 1890
	mir-1185-2	SEQ ID	SEQ ID
		NO: 647	NO: 1891
	mir-1185-1	SEQ ID	SEQ ID
		NO: 646	NO: 1891
	mir-1199	SEQ ID	SEQ ID
		NO: 650	NO: 1892
	mir-1207	SEQ ID	SEQ ID
		NO: 657	NO: 1893
	mir-1224	SEQ ID	SEQ ID
		NO: 659	NO: 1894
	mir-1225	SEQ ID	SEQ ID
		NO: 660	NO: 1895
	mir-1226	SEQ ID	SEQ ID
		NO: 661	NO: 1897
	mir-1227	SEQ ID	SEQ ID
		NO: 662	NO: 1898
	mir-1228	SEQ ID	SEQ ID
		NO: 663	NO: 1899
	mir-1229	SEQ ID	SEQ ID
		NO: 664	NO: 1900
	mir-1233-2	SEQ ID	SEQ ID
		NO: 667	NO: 1901
	mir-1233-1	SEQ ID	SEQ ID
		NO: 666	NO: 1901
	mir-1236	SEQ ID	SEQ ID
		NO: 669	NO: 1902
	mir-1237	SEQ ID	SEQ ID
		NO: 670	NO: 1903
	mir-1238	SEQ ID	SEQ ID
		NO: 671	NO: 1904
	mir-1245b	SEQ ID	SEQ ID
		NO: 677	NO: 1905
	mir-1247	SEQ ID	SEQ ID
		NO: 679	NO: 1907
	mir-1250	SEQ ID	SEQ ID
		NO: 682	NO: 1908
	mir-1251	SEQ ID	SEQ ID
		NO: 683	NO: 1909
	mir-1252	SEQ ID	SEQ ID
		NO: 684	NO: 1910
	mir-1255b-1	SEQ ID	SEQ ID
		NO: 689	NO: 1911
	mir-1255b-2	SEQ ID	SEQ ID
		NO: 690	NO: 1911
	mir-1266	SEQ ID	SEQ ID
		NO: 701	NO: 1915
	mir-1271	SEQ ID	SEQ ID
		NO: 709	NO: 1916
	mir-1273g	SEQ ID	SEQ ID
		NO: 716	NO: 1917
	mir-1273h	SEQ ID	SEQ ID
		NO: 717	NO: 1918
	mir-1277	SEQ ID	SEQ ID
		NO: 720	NO: 1920
	mir-1285-2	SEQ ID	SEQ ID
		NO: 729	NO: 1923
	mir-1285-1	SEQ ID	SEQ ID
		NO: 728	NO: 1923
	mir-1287	SEQ ID	SEQ ID
		NO: 731	NO: 1924
	mir-1288	SEQ ID	SEQ ID
		NO: 732	NO: 1925
	mir-1292	SEQ ID	SEQ ID
		NO: 737	NO: 1926
	mir-1295b	SEQ ID	SEQ ID
		NO: 741	NO: 1927
	mir-1296	SEQ ID	SEQ ID
		NO: 742	NO: 1929
	mir-1298	SEQ ID	SEQ ID
		NO: 744	NO: 1930
	mir-1301	SEQ ID	SEQ ID
		NO: 746	NO: 1931
	mir-1304	SEQ ID	SEQ ID
		NO: 759	NO: 1932
	mir-1306	SEQ ID	SEQ ID
		NO: 761	NO: 1933
	mir-1307	SEQ ID	SEQ ID
		NO: 762	NO: 1934
	mir-1343	SEQ ID	SEQ ID
		NO: 767	NO: 1939
	mir-1468	SEQ ID	SEQ ID
		NO: 768	NO: 1952
	mir-1537	SEQ ID	SEQ ID
		NO: 772	NO: 1962
	mir-1908	SEQ ID	SEQ ID
		NO: 778	NO: 1981
	mir-1909	SEQ ID	SEQ ID
		NO: 779	NO: 1982
	mir-1910	SEQ ID	SEQ ID
		NO: 780	NO: 1984
	mir-1911	SEQ ID	SEQ ID
		NO: 781	NO: 1985
	mir-1914	SEQ ID	SEQ ID
		NO: 784	NO: 1986
	mir-1915	SEQ ID	SEQ ID
		NO: 785	NO: 1987
	mir-2114	SEQ ID	SEQ ID
		NO: 795	NO: 2014
	mir-2115	SEQ ID	SEQ ID
		NO: 796	NO: 2015
	mir-2116	SEQ ID	SEQ ID
		NO: 797	NO: 2017
	mir-2276	SEQ ID	SEQ ID
		NO: 799	NO: 2032
	mir-2277	SEQ ID	SEQ ID
		NO: 800	NO: 2033
	mir-2355	SEQ ID	SEQ ID
		NO: 802	NO: 2034
	mir-2467	SEQ ID	SEQ ID
		NO: 804	NO: 2039
	mir-2681	SEQ ID	SEQ ID
		NO: 805	NO: 2041
	mir-2682	SEQ ID	SEQ ID
		NO: 806	NO: 2042
	mir-3064	SEQ ID	SEQ ID
		NO: 809	NO: 2059
	mir-3065	SEQ ID	SEQ ID
		NO: 810	NO: 2060
	mir-3074	SEQ ID	SEQ ID
		NO: 811	NO: 2061
	mir-3117	SEQ ID	SEQ ID
		NO: 815	NO: 2067
	mir-3120	SEQ ID	SEQ ID
		NO: 824	NO: 2068
	mir-3121	SEQ ID	SEQ ID
		NO: 825	NO: 2069
	mir-3124	SEQ ID	SEQ ID
		NO: 828	NO: 2070
	mir-3126	SEQ ID	SEQ ID
		NO: 830	NO: 2071
	mir-3127	SEQ ID	SEQ ID
		NO: 831	NO: 2072
	mir-3129	SEQ ID	SEQ ID
		NO: 833	NO: 2073
	mir-3130-2	SEQ ID	SEQ ID
		NO: 835	NO: 2074
	mir-3130-1	SEQ ID	SEQ ID
		NO: 834	NO: 2074
	mir-3136	SEQ ID	SEQ ID
		NO: 842	NO: 2075
	mir-3140	SEQ ID	SEQ ID
		NO: 846	NO: 2076
	mir-3144	SEQ ID	SEQ ID
		NO: 850	NO: 2077
	mir-3145	SEQ ID	SEQ ID
		NO: 851	NO: 2078
	mir-3150a	SEQ ID	SEQ ID
		NO: 856	NO: 2079
	mir-3150b	SEQ ID	SEQ ID
		NO: 857	NO: 2080
	mir-3151	SEQ ID	SEQ ID
		NO: 858	NO: 2081
	mir-3152	SEQ ID	SEQ ID
		NO: 859	NO: 2082
	mir-3156-3	SEQ ID	SEQ ID
		NO: 866	NO: 2083
	mir-3156-2	SEQ ID	SEQ ID
		NO: 865	NO: 2083
	mir-3156-1	SEQ ID	SEQ ID
		NO: 864	NO: 2083
	mir-3157	SEQ ID	SEQ ID
		NO: 867	NO: 2084
	mir-3158-2	SEQ ID	SEQ ID
		NO: 869	NO: 2085
	mir-3158-1	SEQ ID	SEQ ID
		NO: 868	NO: 2085
	mir-3160-2	SEQ ID	SEQ ID
		NO: 872	NO: 2087
	mir-3160-1	SEQ ID	SEQ ID
		NO: 871	NO: 2087
	mir-3162	SEQ ID	SEQ ID
		NO: 874	NO: 2088
	mir-3173	SEQ ID	SEQ ID
		NO: 884	NO: 2089
	mir-3177	SEQ ID	SEQ ID
		NO: 888	NO: 2090
	mir-3180-5	SEQ ID	SEQ ID
		NO: 897	NO: 2091
	mir-3180-4	SEQ ID	SEQ ID
		NO: 896	NO: 2091
	mir-3180-3	SEQ ID	SEQ ID
		NO: 895	NO: 2091
	mir-3180-2	SEQ ID	SEQ ID
		NO: 894	NO: 2091
	mir-3180-1	SEQ ID	SEQ ID
		NO: 893	NO: 2091
	mir-3184	SEQ ID	SEQ ID
		NO: 901	NO: 2092
	mir-3186	SEQ ID	SEQ ID
		NO: 903	NO: 2093
	mir-3187	SEQ ID	SEQ ID
		NO: 904	NO: 2094
	mir-3189	SEQ ID	SEQ ID
		NO: 906	NO: 2095
	mir-3190	SEQ ID	SEQ ID
		NO: 907	NO: 2096
	mir-3191	SEQ ID	SEQ ID
		NO: 908	NO: 2097
	mir-3192	SEQ ID	SEQ ID
		NO: 909	NO: 2098
	mir-3194	SEQ ID	SEQ ID
		NO: 911	NO: 2099
	mir-3200	SEQ ID	SEQ ID
		NO: 919	NO: 2100
	mir-3529	SEQ ID	SEQ ID
		NO: 923	NO: 2121
	mir-3591	SEQ ID	SEQ ID
		NO: 924	NO: 2122
	mir-3605	SEQ ID	SEQ ID
		NO: 925	NO: 2123
	mir-3606	SEQ ID	SEQ ID
		NO: 926	NO: 2124
	mir-3607	SEQ ID	SEQ ID
		NO: 927	NO: 2125
	mir-3613	SEQ ID	SEQ ID
		NO: 932	NO: 2126
	mir-3614	SEQ ID	SEQ ID
		NO: 933	NO: 2127
	mir-3616	SEQ ID	SEQ ID
		NO: 935	NO: 2129
	mir-3617	SEQ ID	SEQ ID
		NO: 936	NO: 2130
	mir-3619	SEQ ID	SEQ ID
		NO: 938	NO: 2131
	mir-3620	SEQ ID	SEQ ID
		NO: 939	NO: 2132
	mir-3622a	SEQ ID	SEQ ID
		NO: 941	NO: 2133
	mir-3622b	SEQ ID	SEQ ID
		NO: 942	NO: 2134
	mir-3663	SEQ ID	SEQ ID
		NO: 959	NO: 2139
	mir-3664	SEQ ID	SEQ ID
		NO: 960	NO: 2140
	mir-3667	SEQ ID	SEQ ID
		NO: 963	NO: 2141
	mir-3675	SEQ ID	SEQ ID
		NO: 972	NO: 2142
	mir-3677	SEQ ID	SEQ ID
		NO: 973	NO: 2144
	mir-3678	SEQ ID	SEQ ID
		NO: 974	NO: 2145
	mir-3679	SEQ ID	SEQ ID
		NO: 975	NO: 2146
	mir-3680-2	SEQ ID	SEQ ID
		NO: 977	NO: 2147
	mir-3680-1	SEQ ID	SEQ ID
		NO: 976	NO: 2147
	mir-3681	SEQ ID	SEQ ID
		NO: 978	NO: 2148
	mir-3682	SEQ ID	SEQ ID
		NO: 979	NO: 2149
	mir-3688-2	SEQ ID	SEQ ID
		NO: 986	NO: 2150
	mir-3688-1	SEQ ID	SEQ ID
		NO: 985	NO: 2150
	mir-3689a	SEQ ID	SEQ ID
		NO: 987	NO: 2151
	mir-3689b	SEQ ID	SEQ ID
		NO: 988	NO: 2152
	mir-3691	SEQ ID	SEQ ID
		NO: 996	NO: 2153
	mir-3692	SEQ ID	SEQ ID
		NO: 997	NO: 2154
	mir-3912	SEQ ID	SEQ ID
		NO: 1006	NO: 2175
	mir-3913-2	SEQ ID	SEQ ID
		NO: 1008	NO: 2176
	mir-3913-1	SEQ ID	SEQ ID
		NO: 1007	NO: 2176
	mir-3922	SEQ ID	SEQ ID
		NO: 1018	NO: 2177
	mir-3925	SEQ ID	SEQ ID
		NO: 1021	NO: 2178
	mir-3927	SEQ ID	SEQ ID
		NO: 1024	NO: 2179
	mir-3928	SEQ ID	SEQ ID
		NO: 1025	NO: 2180
	mir-3934	SEQ ID	SEQ ID
		NO: 1027	NO: 2181
	mir-3940	SEQ ID	SEQ ID
		NO: 1033	NO: 2182
	mir-3942	SEQ ID	SEQ ID
		NO: 1035	NO: 2183
	mir-3944	SEQ ID	SEQ ID
		NO: 1037	NO: 2184
	mir-4423	SEQ ID	SEQ ID
		NO: 1136	NO: 2195
	mir-4433b	SEQ ID	SEQ ID
		NO: 1147	NO: 2197
	mir-4433	SEQ ID	SEQ ID
		NO: 1146	NO: 2196
	mir-4436b-1	SEQ ID	SEQ ID
		NO: 1152	NO: 2198
	mir-4436b-2	SEQ ID	SEQ ID
		NO: 1153	NO: 2198
	mir-4445	SEQ ID	SEQ ID
		NO: 1163	NO: 2199
	mir-4446	SEQ ID	SEQ ID
		NO: 1164	NO: 2200
	mir-4474	SEQ ID	SEQ ID
		NO: 1193	NO: 2201
	mir-4482	SEQ ID	SEQ ID
		NO: 1202	NO: 2202
	mir-4520a	SEQ ID	SEQ ID
		NO: 1242	NO: 2207
	mir-4520b	SEQ ID	SEQ ID
		NO: 1243	NO: 2208
	mir-4524a	SEQ ID	SEQ ID
		NO: 1247	NO: 2209
	mir-4524b	SEQ ID	SEQ ID
		NO: 1248	NO: 2210
	mir-4529	SEQ ID	SEQ ID
		NO: 1253	NO: 2212
	mir-4536-2	SEQ ID	SEQ ID
		NO: 1261	NO: 2213
	mir-4536-1	SEQ ID	SEQ ID
		NO: 1260	NO: 2213
	mir-4632	SEQ ID	SEQ ID
		NO: 1266	NO: 2216
	mir-4633	SEQ ID	SEQ ID
		NO: 1267	NO: 2217
	mir-4638	SEQ ID	SEQ ID
		NO: 1272	NO: 2218
	mir-4639	SEQ ID	SEQ ID
		NO: 1273	NO: 2219
	mir-4640	SEQ ID	SEQ ID
		NO: 1274	NO: 2220
	mir-4645	SEQ ID	SEQ ID
		NO: 1279	NO: 2221
	mir-4646	SEQ ID	SEQ ID
		NO: 1280	NO: 2222
	mir-4649	SEQ ID	SEQ ID
		NO: 1283	NO: 2223
	mir-4650-2	SEQ ID	SEQ ID
		NO: 1285	NO: 2224
	mir-4650-1	SEQ ID	SEQ ID
		NO: 1284	NO: 2224
	mir-4652	SEQ ID	SEQ ID
		NO: 1287	NO: 2225
	mir-4653	SEQ ID	SEQ ID
		NO: 1288	NO: 2226
	mir-4655	SEQ ID	SEQ ID
		NO: 1290	NO: 2227
	mir-4659a	SEQ ID	SEQ ID
		NO: 1294	NO: 2228
	mir-4659b	SEQ ID	SEQ ID
		NO: 1295	NO: 2229
	mir-4661	SEQ ID	SEQ ID
		NO: 1297	NO: 2230
	mir-4662a	SEQ ID	SEQ ID
		NO: 1298	NO: 2231
	mir-4664	SEQ ID	SEQ ID
		NO: 1301	NO: 2232
	mir-4665	SEQ ID	SEQ ID
		NO: 1302	NO: 2233
	mir-4666a	SEQ ID	SEQ ID
		NO: 1303	NO: 2234
	mir-4667	SEQ ID	SEQ ID
		NO: 1305	NO: 2235
	mir-4668	SEQ ID	SEQ ID
		NO: 1306	NO: 2236
	mir-4670	SEQ ID	SEQ ID
		NO: 1308	NO: 2237
	mir-4671	SEQ ID	SEQ ID
		NO: 1309	NO: 2238
	mir-4676	SEQ ID	SEQ ID
		NO: 1314	NO: 2239
	mir-4677	SEQ ID	SEQ ID
		NO: 1315	NO: 2240
	mir-4680	SEQ ID	SEQ ID
		NO: 1319	NO: 2241
	mir-4684	SEQ ID	SEQ ID
		NO: 1323	NO: 2242
	mir-4685	SEQ ID	SEQ ID
		NO: 1324	NO: 2243
	mir-4687	SEQ ID	SEQ ID
		NO: 1326	NO: 2244
	mir-4690	SEQ ID	SEQ ID
		NO: 1329	NO: 2245
	mir-4691	SEQ ID	SEQ ID
		NO: 1330	NO: 2246
	mir-4693	SEQ ID	SEQ ID
		NO: 1332	NO: 2247
	mir-4694	SEQ ID	SEQ ID
		NO: 1333	NO: 2248
	mir-4695	SEQ ID	SEQ ID
		NO: 1334	NO: 2249
	mir-4697	SEQ ID	SEQ ID
		NO: 1336	NO: 2250
	mir-4699	SEQ ID	SEQ ID
		NO: 1338	NO: 2251
	mir-4700	SEQ ID	SEQ ID
		NO: 1339	NO: 2252
	mir-4701	SEQ ID	SEQ ID
		NO: 1340	NO: 2253
	mir-4703	SEQ ID	SEQ ID
		NO: 1341	NO: 2254
	mir-4704	SEQ ID	SEQ ID
		NO: 1342	NO: 2255
	mir-4707	SEQ ID	SEQ ID
		NO: 1345	NO: 2256
	mir-4708	SEQ ID	SEQ ID
		NO: 1346	NO: 2257
	mir-4709	SEQ ID	SEQ ID
		NO: 1347	NO: 2258
	mir-4711	SEQ ID	SEQ ID
		NO: 1349	NO: 2259
	mir-4712	SEQ ID	SEQ ID
		NO: 1350	NO: 2260
	mir-4713	SEQ ID	SEQ ID
		NO: 1351	NO: 2261
	mir-4714	SEQ ID	SEQ ID
		NO: 1352	NO: 2262
	mir-4715	SEQ ID	SEQ ID
		NO: 1353	NO: 2263
	mir-4716	SEQ ID	SEQ ID
		NO: 1354	NO: 2264
	mir-4717	SEQ ID	SEQ ID
		NO: 1355	NO: 2265
	mir-4720	SEQ ID	SEQ ID
		NO: 1358	NO: 2266
	mir-4722	SEQ ID	SEQ ID
		NO: 1360	NO: 2267
	mir-4723	SEQ ID	SEQ ID
		NO: 1361	NO: 2268
	mir-4724	SEQ ID	SEQ ID
		NO: 1362	NO: 2269
	mir-4725	SEQ ID	SEQ ID
		NO: 1363	NO: 2270
	mir-4726	SEQ ID	SEQ ID
		NO: 1364	NO: 2271
	mir-4727	SEQ ID	SEQ ID
		NO: 1365	NO: 2272
	mir-4728	SEQ ID	SEQ ID
		NO: 1366	NO: 2273
	mir-4731	SEQ ID	SEQ ID
		NO: 1369	NO: 2274
	mir-4732	SEQ ID	SEQ ID
		NO: 1370	NO: 2275
	mir-4733	SEQ ID	SEQ ID
		NO: 1371	NO: 2276
	mir-4735	SEQ ID	SEQ ID
		NO: 1373	NO: 2277
	mir-4738	SEQ ID	SEQ ID
		NO: 1376	NO: 2278
	mir-4740	SEQ ID	SEQ ID
		NO: 1378	NO: 2279
	mir-4742	SEQ ID	SEQ ID
		NO: 1380	NO: 2280
	mir-4743	SEQ ID	SEQ ID
		NO: 1381	NO: 2281
	mir-4745	SEQ ID	SEQ ID
		NO: 1383	NO: 2282
	mir-4746	SEQ ID	SEQ ID
		NO: 1384	NO: 2283
	mir-4747	SEQ ID	SEQ ID
		NO: 1385	NO: 2284
	mir-4749	SEQ ID	SEQ ID
		NO: 1387	NO: 2285
	mir-4750	SEQ ID	SEQ ID
		NO: 1388	NO: 2286
	mir-4753	SEQ ID	SEQ ID
		NO: 1391	NO: 2287
	mir-4755	SEQ ID	SEQ ID
		NO: 1393	NO: 2288
	mir-4756	SEQ ID	SEQ ID
		NO: 1394	NO: 2289
	mir-4757	SEQ ID	SEQ ID
		NO: 1395	NO: 2290
	mir-4758	SEQ ID	SEQ ID
		NO: 1396	NO: 2291
	mir-4760	SEQ ID	SEQ ID
		NO: 1398	NO: 2292
	mir-4761	SEQ ID	SEQ ID
		NO: 1399	NO: 2293
	mir-4762	SEQ ID	SEQ ID
		NO: 1400	NO: 2294
	mir-4763	SEQ ID	SEQ ID
		NO: 1401	NO: 2295
	mir-4764	SEQ ID	SEQ ID
		NO: 1402	NO: 2296
	mir-4766	SEQ ID	SEQ ID
		NO: 1404	NO: 2297
	mir-4768	SEQ ID	SEQ ID
		NO: 1406	NO: 2298
	mir-4769	SEQ ID	SEQ ID
		NO: 1407	NO: 2299
	mir-4772	SEQ ID	SEQ ID
		NO: 1411	NO: 2300
	mir-4774	SEQ ID	SEQ ID
		NO: 1414	NO: 2301
	mir-4776-2	SEQ ID	SEQ ID
		NO: 1417	NO: 2302
	mir-4776-1	SEQ ID	SEQ ID
		NO: 1416	NO: 2302
	mir-4777	SEQ ID	SEQ ID
		NO: 1418	NO: 2303
	mir-4778	SEQ ID	SEQ ID
		NO: 1419	NO: 2304
	mir-4781	SEQ ID	SEQ ID
		NO: 1422	NO: 2305
	mir-4782	SEQ ID	SEQ ID
		NO: 1423	NO: 2306
	mir-4783	SEQ ID	SEQ ID
		NO: 1424	NO: 2307
	mir-4786	SEQ ID	SEQ ID
		NO: 1427	NO: 2308
	mir-4787	SEQ ID	SEQ ID
		NO: 1428	NO: 2309
	mir-4789	SEQ ID	SEQ ID
		NO: 1430	NO: 2310
	mir-4790	SEQ ID	SEQ ID
		NO: 1431	NO: 2311
	mir-4793	SEQ ID	SEQ ID
		NO: 1434	NO: 2312
	mir-4795	SEQ ID	SEQ ID
		NO: 1436	NO: 2313
	mir-4796	SEQ ID	SEQ ID
		NO: 1437	NO: 2314
	mir-4797	SEQ ID	SEQ ID
		NO: 1438	NO: 2315
	mir-4798	SEQ ID	SEQ ID
		NO: 1439	NO: 2316
	mir-4799	SEQ ID	SEQ ID
		NO: 1440	NO: 2317
	mir-4800	SEQ ID	SEQ ID
		NO: 1441	NO: 2318
	mir-4802	SEQ ID	SEQ ID
		NO: 1443	NO: 2319
	mir-4804	SEQ ID	SEQ ID
		NO: 1445	NO: 2320
	mir-4999	SEQ ID	SEQ ID
		NO: 1446	NO: 2334
	mir-5000	SEQ ID	SEQ ID
		NO: 1447	NO: 2337
	mir-5001	SEQ ID	SEQ ID
		NO: 1448	NO: 2338
	mir-5002	SEQ ID	SEQ ID
		NO: 1449	NO: 2339
	mir-5003	SEQ ID	SEQ ID
		NO: 1450	NO: 2340
	mir-5004	SEQ ID	SEQ ID
		NO: 1451	NO: 2341
	mir-5006	SEQ ID	SEQ ID
		NO: 1452	NO: 2342
	mir-5007	SEQ ID	SEQ ID
		NO: 1453	NO: 2343
	mir-5008	SEQ ID	SEQ ID
		NO: 1454	NO: 2344
	mir-5009	SEQ ID	SEQ ID
		NO: 1455	NO: 2345
	mir-5010	SEQ ID	SEQ ID
		NO: 1456	NO: 2348
	mir-5011	SEQ ID	SEQ ID
		NO: 1457	NO: 2349
	mir-5088	SEQ ID	SEQ ID
		NO: 1460	NO: 2357
	mir-5089	SEQ ID	SEQ ID
		NO: 1461	NO: 2358
	mir-5187	SEQ ID	SEQ ID
		NO: 1471	NO: 2373
	mir-5189	SEQ ID	SEQ ID
		NO: 1473	NO: 2374
	mir-5195	SEQ ID	SEQ ID
		NO: 1479	NO: 2380
	mir-5196	SEQ ID	SEQ ID
		NO: 1480	NO: 2381
	mir-5197	SEQ ID	SEQ ID
		NO: 1481	NO: 2382
	mir-5571	SEQ ID	SEQ ID
		NO: 1482	NO: 2434
	mir-5579	SEQ ID	SEQ ID
		NO: 1484	NO: 2435
	mir-5580	SEQ ID	SEQ ID
		NO: 1485	NO: 2436
	mir-5581	SEQ ID	SEQ ID
		NO: 1486	NO: 2437
	mir-5582	SEQ ID	SEQ ID
		NO: 1487	NO: 2438
	mir-5583-2	SEQ ID	SEQ ID
		NO: 1489	NO: 2439
	mir-5583-1	SEQ ID	SEQ ID
		NO: 1488	NO: 2439
	mir-5584	SEQ ID	SEQ ID
		NO: 1490	NO: 2440
	mir-5585	SEQ ID	SEQ ID
		NO: 1491	NO: 2441
	mir-5586	SEQ ID	SEQ ID
		NO: 1492	NO: 2442
	mir-5587	SEQ ID	SEQ ID
		NO: 1493	NO: 2443
	mir-5588	SEQ ID	SEQ ID
		NO: 1494	NO: 2444
	mir-5589	SEQ ID	SEQ ID
		NO: 1495	NO: 2445
	mir-5590	SEQ ID	SEQ ID
		NO: 1496	NO: 2446
	mir-5591	SEQ ID	SEQ ID
		NO: 1497	NO: 2447
	mir-5699	SEQ ID	SEQ ID
		NO: 1521	NO: 2449
	mir-6499	SEQ ID	SEQ ID
		NO: 1571	NO: 2474
	mir-6500	SEQ ID	SEQ ID
		NO: 1572	NO: 2475
	mir-6501	SEQ ID	SEQ ID
		NO: 1573	NO: 2476
	mir-6502	SEQ ID	SEQ ID
		NO: 1574	NO: 2477
	mir-6503	SEQ ID	SEQ ID
		NO: 1575	NO: 2478
	mir-6504	SEQ ID	SEQ ID
		NO: 1576	NO: 2479
	mir-6505	SEQ ID	SEQ ID
		NO: 1577	NO: 2480
	mir-6506	SEQ ID	SEQ ID
		NO: 1578	NO: 2481
	mir-6507	SEQ ID	SEQ ID
		NO: 1579	NO: 2482
	mir-6508	SEQ ID	SEQ ID
		NO: 1580	NO: 2483
	mir-6509	SEQ ID	SEQ ID
		NO: 1581	NO: 2484
	mir-6510	SEQ ID	SEQ ID
		NO: 1582	NO: 2485
	mir-6511a-1	SEQ ID	SEQ ID
		NO: 1583	NO: 2486
	mir-6511a-2	SEQ ID	SEQ ID
		NO: 1584	NO: 2486
	mir-6511a-3	SEQ ID	SEQ ID
		NO: 1585	NO: 2486
	mir-6511a-4	SEQ ID	SEQ ID
		NO: 1586	NO: 2486
	mir-6511b-1	SEQ ID	SEQ ID
		NO: 1587	NO: 2487
	mir-6511b-2	SEQ ID	SEQ ID
		NO: 1588	NO: 2487
	mir-6512	SEQ ID	SEQ ID
		NO: 1589	NO: 2488
	mir-6513	SEQ ID	SEQ ID
		NO: 1590	NO: 2489
	mir-6514	SEQ ID	SEQ ID
		NO: 1591	NO: 2490
	mir-6515	SEQ ID	SEQ ID
		NO: 1592	NO: 2491
	mir-6516	SEQ ID	SEQ ID
		NO: 1593	NO: 2493
	mir-6715b	SEQ ID	SEQ ID
		NO: 1595	NO: 2505
	mir-6716	SEQ ID	SEQ ID
		NO: 1596	NO: 2507
	mir-6717	SEQ ID	SEQ ID
		NO: 1597	NO: 2508
	mir-6718	SEQ ID	SEQ ID
		NO: 1598	NO: 2509
	mir-6720	SEQ ID	SEQ ID
		NO: 1600	NO: 2510
	mir-6721	SEQ ID	SEQ ID
		NO: 1601	NO: 2511
	mir-6722	SEQ ID	SEQ ID
		NO: 1602	NO: 2512
	mir-6723	SEQ ID	SEQ ID
		NO: 1603	NO: 2513
	mir-6724	SEQ ID	SEQ ID
		NO: 1604	NO: 2514
	mir-6726	SEQ ID	SEQ ID
		NO: 1605	NO: 2515
	mir-6727	SEQ ID	SEQ ID
		NO: 1606	NO: 2516
	mir-6728	SEQ ID	SEQ ID
		NO: 1607	NO: 2517
	mir-6729	SEQ ID	SEQ ID
		NO: 1608	NO: 2518
	mir-6730	SEQ ID	SEQ ID
		NO: 1609	NO: 2519
	mir-6731	SEQ ID	SEQ ID
		NO: 1610	NO: 2520
	mir-6732	SEQ ID	SEQ ID
		NO: 1611	NO: 2521
	mir-6733	SEQ ID	SEQ ID
		NO: 1612	NO: 2522
	mir-6734	SEQ ID	SEQ ID
		NO: 1613	NO: 2523
	mir-6735	SEQ ID	SEQ ID
		NO: 1614	NO: 2524
	mir-6736	SEQ ID	SEQ ID
		NO: 1615	NO: 2525
	mir-6737	SEQ ID	SEQ ID
		NO: 1616	NO: 2526
	mir-6738	SEQ ID	SEQ ID
		NO: 1617	NO: 2527
	mir-6739	SEQ ID	SEQ ID
		NO: 1618	NO: 2528
	mir-6740	SEQ ID	SEQ ID
		NO: 1619	NO: 2529
	mir-6741	SEQ ID	SEQ ID
		NO: 1620	NO: 2530
	mir-6742	SEQ ID	SEQ ID
		NO: 1621	NO: 2531
	mir-6743	SEQ ID	SEQ ID
		NO: 1622	NO: 2532
	mir-6744	SEQ ID	SEQ ID
		NO: 1623	NO: 2533
	mir-6746	SEQ ID	SEQ ID
		NO: 1625	NO: 2534
	mir-6747	SEQ ID	SEQ ID
		NO: 1626	NO: 2535
	mir-6748	SEQ ID	SEQ ID
		NO: 1627	NO: 2536
	mir-6749	SEQ ID	SEQ ID
		NO: 1628	NO: 2537
	mir-6750	SEQ ID	SEQ ID
		NO: 1629	NO: 2538
	mir-6751	SEQ ID	SEQ ID
		NO: 1630	NO: 2539
	mir-6752	SEQ ID	SEQ ID
		NO: 1631	NO: 2540
	mir-6753	SEQ ID	SEQ ID
		NO: 1632	NO: 2541
	mir-6754	SEQ ID	SEQ ID
		NO: 1633	NO: 2542
	mir-6755	SEQ ID	SEQ ID
		NO: 1634	NO: 2543
	mir-6756	SEQ ID	SEQ ID
		NO: 1635	NO: 2545
	mir-6757	SEQ ID	SEQ ID
		NO: 1636	NO: 2546
	mir-6758	SEQ ID	SEQ ID
		NO: 1637	NO: 2547
	mir-6759	SEQ ID	SEQ ID
		NO: 1638	NO: 2548
	mir-6760	SEQ ID	SEQ ID
		NO: 1639	NO: 2549
	mir-6761	SEQ ID	SEQ ID
		NO: 1640	NO: 2550
	mir-6762	SEQ ID	SEQ ID
		NO: 1641	NO: 2551
	mir-6763	SEQ ID	SEQ ID
		NO: 1642	NO: 2552
	mir-6764	SEQ ID	SEQ ID
		NO: 1643	NO: 2553
	mir-6765	SEQ ID	SEQ ID
		NO: 1644	NO: 2554
	mir-6766	SEQ ID	SEQ ID
		NO: 1645	NO: 2556
	mir-6767	SEQ ID	SEQ ID
		NO: 1646	NO: 2557
	mir-6768	SEQ ID	SEQ ID
		NO: 1647	NO: 2558
	mir-6769a	SEQ ID	SEQ ID
		NO: 1648	NO: 2559
	mir-6769b	SEQ ID	SEQ ID
		NO: 1649	NO: 2560
	mir-6770-3	SEQ ID	SEQ ID
		NO: 1652	NO: 2561
	mir-6770-2	SEQ ID	SEQ ID
		NO: 1651	NO: 2561
	mir-6770-1	SEQ ID	SEQ ID
		NO: 1650	NO: 2561
	mir-6771	SEQ ID	SEQ ID
		NO: 1653	NO: 2562
	mir-6772	SEQ ID	SEQ ID
		NO: 1654	NO: 2563
	mir-6773	SEQ ID	SEQ ID
		NO: 1655	NO: 2564
	mir-6774	SEQ ID	SEQ ID
		NO: 1656	NO: 2565
	mir-6775	SEQ ID	SEQ ID
		NO: 1657	NO: 2566
	mir-6776	SEQ ID	SEQ ID
		NO: 1658	NO: 2567
	mir-6777	SEQ ID	SEQ ID
		NO: 1659	NO: 2568
	mir-6778	SEQ ID	SEQ ID
		NO: 1660	NO: 2569
	mir-6779	SEQ ID	SEQ ID
		NO: 1661	NO: 2570
	mir-6780a	SEQ ID	SEQ ID
		NO: 1662	NO: 2571
	mir-6780b	SEQ ID	SEQ ID
		NO: 1663	NO: 2572
	mir-6781	SEQ ID	SEQ ID
		NO: 1664	NO: 2573
	mir-6782	SEQ ID	SEQ ID
		NO: 1665	NO: 2574
	mir-6783	SEQ ID	SEQ ID
		NO: 1666	NO: 2575
	mir-6784	SEQ ID	SEQ ID
		NO: 1667	NO: 2576
	mir-6785	SEQ ID	SEQ ID
		NO: 1668	NO: 2577
	mir-6786	SEQ ID	SEQ ID
		NO: 1669	NO: 2578
	mir-6787	SEQ ID	SEQ ID
		NO: 1670	NO: 2579
	mir-6788	SEQ ID	SEQ ID
		NO: 1671	NO: 2580
	mir-6789	SEQ ID	SEQ ID
		NO: 1672	NO: 2581
	mir-6790	SEQ ID	SEQ ID
		NO: 1673	NO: 2582
	mir-6791	SEQ ID	SEQ ID
		NO: 1674	NO: 2583
	mir-6792	SEQ ID	SEQ ID
		NO: 1675	NO: 2584
	mir-6793	SEQ ID	SEQ ID
		NO: 1676	NO: 2585
	mir-6794	SEQ ID	SEQ ID
		NO: 1677	NO: 2586
	mir-6795	SEQ ID	SEQ ID
		NO: 1678	NO: 2587
	mir-6796	SEQ ID	SEQ ID
		NO: 1679	NO: 2588
	mir-6797	SEQ ID	SEQ ID
		NO: 1680	NO: 2589
	mir-6798	SEQ ID	SEQ ID
		NO: 1681	NO: 2590
	mir-6799	SEQ ID	SEQ ID
		NO: 1682	NO: 2591
	mir-6800	SEQ ID	SEQ ID
		NO: 1683	NO: 2592
	mir-6801	SEQ ID	SEQ ID
		NO: 1684	NO: 2593
	mir-6802	SEQ ID	SEQ ID
		NO: 1685	NO: 2594
	mir-6803	SEQ ID	SEQ ID
		NO: 1686	NO: 2595
	mir-6804	SEQ ID	SEQ ID
		NO: 1687	NO: 2596
	mir-6805	SEQ ID	SEQ ID
		NO: 1688	NO: 2597
	mir-6806	SEQ ID	SEQ ID
		NO: 1689	NO: 2598
	mir-6807	SEQ ID	SEQ ID
		NO: 1690	NO: 2599
	mir-6808	SEQ ID	SEQ ID
		NO: 1691	NO: 2600
	mir-6809	SEQ ID	SEQ ID
		NO: 1692	NO: 2601
	mir-6810	SEQ ID	SEQ ID
		NO: 1693	NO: 2602
	mir-6811	SEQ ID	SEQ ID
		NO: 1694	NO: 2603
	mir-6812	SEQ ID	SEQ ID
		NO: 1695	NO: 2604
	mir-6813	SEQ ID	SEQ ID
		NO: 1696	NO: 2605
	mir-6814	SEQ ID	SEQ ID
		NO: 1697	NO: 2606
	mir-6815	SEQ ID	SEQ ID
		NO: 1698	NO: 2607
	mir-6816	SEQ ID	SEQ ID
		NO: 1699	NO: 2608
	mir-6817	SEQ ID	SEQ ID
		NO: 1700	NO: 2609
	mir-6818	SEQ ID	SEQ ID
		NO: 1701	NO: 2610
	mir-6819	SEQ ID	SEQ ID
		NO: 1702	NO: 2611
	mir-6820	SEQ ID	SEQ ID
		NO: 1703	NO: 2612
	mir-6821	SEQ ID	SEQ ID
		NO: 1704	NO: 2613
	mir-6822	SEQ ID	SEQ ID
		NO: 1705	NO: 2614
	mir-6823	SEQ ID	SEQ ID
		NO: 1706	NO: 2615
	mir-6824	SEQ ID	SEQ ID
		NO: 1707	NO: 2616
	mir-6825	SEQ ID	SEQ ID
		NO: 1708	NO: 2617
	mir-6826	SEQ ID	SEQ ID
		NO: 1709	NO: 2618
	mir-6827	SEQ ID	SEQ ID
		NO: 1710	NO: 2619
	mir-6828	SEQ ID	SEQ ID
		NO: 1711	NO: 2620
	mir-6829	SEQ ID	SEQ ID
		NO: 1712	NO: 2621
	mir-6830	SEQ ID	SEQ ID
		NO: 1713	NO: 2622
	mir-6831	SEQ ID	SEQ ID
		NO: 1714	NO: 2623
	mir-6832	SEQ ID	SEQ ID
		NO: 1715	NO: 2624
	mir-6833	SEQ ID	SEQ ID
		NO: 1716	NO: 2625
	mir-6834	SEQ ID	SEQ ID
		NO: 1717	NO: 2626
	mir-6835	SEQ ID	SEQ ID
		NO: 1718	NO: 2627
	mir-6836	SEQ ID	SEQ ID
		NO: 1719	NO: 2628
	mir-6837	SEQ ID	SEQ ID
		NO: 1720	NO: 2629
	mir-6838	SEQ ID	SEQ ID
		NO: 1721	NO: 2630
	mir-6839	SEQ ID	SEQ ID
		NO: 1722	NO: 2631
	mir-6840	SEQ ID	SEQ ID
		NO: 1723	NO: 2632
	mir-6841	SEQ ID	SEQ ID
		NO: 1724	NO: 2633
	mir-6842	SEQ ID	SEQ ID
		NO: 1725	NO: 2634
	mir-6845	SEQ ID	SEQ ID
		NO: 1728	NO: 2635
	mir-6846	SEQ ID	SEQ ID
		NO: 1729	NO: 2636
	mir-6847	SEQ ID	SEQ ID
		NO: 1730	NO: 2637
	mir-6848	SEQ ID	SEQ ID
		NO: 1731	NO: 2638
	mir-6849	SEQ ID	SEQ ID
		NO: 1732	NO: 2639
	mir-6850	SEQ ID	SEQ ID
		NO: 1733	NO: 2640
	mir-6851	SEQ ID	SEQ ID
		NO: 1734	NO: 2641
	mir-6852	SEQ ID	SEQ ID
		NO: 1735	NO: 2642
	mir-6853	SEQ ID	SEQ ID
		NO: 1736	NO: 2643
	mir-6854	SEQ ID	SEQ ID
		NO: 1737	NO: 2644
	mir-6855	SEQ ID	SEQ ID
		NO: 1738	NO: 2645
	mir-6856	SEQ ID	SEQ ID
		NO: 1739	NO: 2646
	mir-6857	SEQ ID	SEQ ID
		NO: 1740	NO: 2647
	mir-6858	SEQ ID	SEQ ID
		NO: 1741	NO: 2648
	mir-6859-3	SEQ ID	SEQ ID
		NO: 1744	NO: 2649
	mir-6859-2	SEQ ID	SEQ ID
		NO: 1743	NO: 2649
	mir-6859-1	SEQ ID	SEQ ID
		NO: 1742	NO: 2649
	mir-6861	SEQ ID	SEQ ID
		NO: 1746	NO: 2650
	mir-6862-2	SEQ ID	SEQ ID
		NO: 1748	NO: 2651
	mir-6862-1	SEQ ID	SEQ ID
		NO: 1747	NO: 2651
	mir-6864	SEQ ID	SEQ ID
		NO: 1750	NO: 2652
	mir-6865	SEQ ID	SEQ ID
		NO: 1751	NO: 2653
	mir-6866	SEQ ID	SEQ ID
		NO: 1752	NO: 2654
	mir-6867	SEQ ID	SEQ ID
		NO: 1753	NO: 2655
	mir-6868	SEQ ID	SEQ ID
		NO: 1754	NO: 2656
	mir-6869	SEQ ID	SEQ ID
		NO: 1755	NO: 2657
	mir-6870	SEQ ID	SEQ ID
		NO: 1756	NO: 2658
	mir-6871	SEQ ID	SEQ ID
		NO: 1757	NO: 2659
	mir-6872	SEQ ID	SEQ ID
		NO: 1758	NO: 2660
	mir-6873	SEQ ID	SEQ ID
		NO: 1759	NO: 2661
	mir-6874	SEQ ID	SEQ ID
		NO: 1760	NO: 2662
	mir-6875	SEQ ID	SEQ ID
		NO: 1761	NO: 2663
	mir-6876	SEQ ID	SEQ ID
		NO: 1762	NO: 2664
	mir-6877	SEQ ID	SEQ ID
		NO: 1763	NO: 2665
	mir-6878	SEQ ID	SEQ ID
		NO: 1764	NO: 2666
	mir-6879	SEQ ID	SEQ ID
		NO: 1765	NO: 2667
	mir-6880	SEQ ID	SEQ ID
		NO: 1766	NO: 2668
	mir-6881	SEQ ID	SEQ ID
		NO: 1767	NO: 2669
	mir-6882	SEQ ID	SEQ ID
		NO: 1768	NO: 2670
	mir-6883	SEQ ID	SEQ ID
		NO: 1769	NO: 2671
	mir-6884	SEQ ID	SEQ ID
		NO: 1770	NO: 2672
	mir-6885	SEQ ID	SEQ ID
		NO: 1771	NO: 2673
	mir-6886	SEQ ID	SEQ ID
		NO: 1772	NO: 2674
	mir-6887	SEQ ID	SEQ ID
		NO: 1773	NO: 2675
	mir-6888	SEQ ID	SEQ ID
		NO: 1774	NO: 2676
	mir-6889	SEQ ID	SEQ ID
		NO: 1775	NO: 2677
	mir-6890	SEQ ID	SEQ ID
		NO: 1776	NO: 2678
	mir-6891	SEQ ID	SEQ ID
		NO: 1777	NO: 2679
	mir-6892	SEQ ID	SEQ ID
		NO: 1778	NO: 2680
	mir-6893	SEQ ID	SEQ ID
		NO: 1779	NO: 2681
	mir-6894	SEQ ID	SEQ ID
		NO: 1780	NO: 2682
	mir-6895	SEQ ID	SEQ ID
		NO: 1781	NO: 2683
	mir-7106	SEQ ID	SEQ ID
		NO: 1782	NO: 2685
	mir-7107	SEQ ID	SEQ ID
		NO: 1783	NO: 2686
	mir-7108	SEQ ID	SEQ ID
		NO: 1784	NO: 2687
	mir-7109	SEQ ID	SEQ ID
		NO: 1785	NO: 2688
	mir-7110	SEQ ID	SEQ ID
		NO: 1786	NO: 2689
	mir-7111	SEQ ID	SEQ ID
		NO: 1787	NO: 2690
	mir-7112-2	SEQ ID	SEQ ID
		NO: 1789	NO: 2691
	mir-7112-1	SEQ ID	SEQ ID
		NO: 1788	NO: 2691
	mir-7113	SEQ ID	SEQ ID
		NO: 1790	NO: 2692
	mir-7114	SEQ ID	SEQ ID
		NO: 1791	NO: 2693
	mir-7151	SEQ ID	SEQ ID
		NO: 1793	NO: 2694
	mir-7152	SEQ ID	SEQ ID
		NO: 1794	NO: 2695
	mir-7153	SEQ ID	SEQ ID
		NO: 1795	NO: 2696
	mir-7154	SEQ ID	SEQ ID
		NO: 1796	NO: 2697
	mir-7155	SEQ ID	SEQ ID
		NO: 1797	NO: 2698
	mir-7156	SEQ ID	SEQ ID
		NO: 1798	NO: 2699
	mir-7157	SEQ ID	SEQ ID
		NO: 1799	NO: 2700
	mir-7158	SEQ ID	SEQ ID
		NO: 1800	NO: 2701
	mir-7159	SEQ ID	SEQ ID
		NO: 1801	NO: 2702
	mir-7160	SEQ ID	SEQ ID
		NO: 1802	NO: 2703
	mir-7161	SEQ ID	SEQ ID
		NO: 1803	NO: 2704
	mir-7162	SEQ ID	SEQ ID
		NO: 1804	NO: 2705
	mir-7843	SEQ ID	SEQ ID
		NO: 1813	NO: 2713
	mir-7844	SEQ ID	SEQ ID
		NO: 1814	NO: 2714
	mir-7845	SEQ ID	SEQ ID
		NO: 1815	NO: 2715
	mir-7850	SEQ ID	SEQ ID
		NO: 1820	NO: 2716
	mir-7853	SEQ ID	SEQ ID
		NO: 1823	NO: 2717
	mir-7855	SEQ ID	SEQ ID
		NO: 1825	NO: 2718
	mir-7856	SEQ ID	SEQ ID
		NO: 1826	NO: 2719

As noted, the preceding table is based on the 5′ sequence of the particular RNA. If the '3 prime sequence is used to calculate the Drosha cutting site, overhang positions should be accounted for. For example, if the 3′ sequence has one nucleotide overhang, positions 5 and 9-12 would correspond to positions 6 and 10-13. If the 3′ sequence has two nucleotide overhangs, positions 5 and 9-12 would correspond to positions 7 and 11-14. If the 3′ sequence has three nucleotide overhangs, positions 5 and 9-12 would correspond to 8 and 12-15.

Counting to define the Drosha cutting site can also be based on an in silico folding of the miRNA stem loop sequence, such as minimum free energy folding. In these examples, counting can be started by assigning position 1 to the first nucleotide on the 5′ strand by the Drosha cutting site in the pre-miRNA portion of the pri-miRNA. Then position numbers can be further assigned along the hairpin moving towards the terminal loop and taking note if the nucleotides are mismatched or matched. In cases where there is an asymmetric mismatch, i.e. one strand contains more nucleotides than the other in a mismatch position, position can be assigned based on the shorter strand. If the asymmetric mismatch has a conformation where one strand contains no mismatched nucleotides, but the other strand does, then the mismatch can be assigned to the higher position. In cases where an assymetric mismatch is located at position 1, the positions can be assigned according to the 5′ strand until a matched position is encountered.

FIG. 17 provides examples of counting based on the description in the preceding paragraph. In these examples, the upper sequences contain part of the pri-miRNA sequence, consisting of the pre-miRNA portion and part of the flanking sequence. Below the sequence the folded hairpin is depicted where the upper left part of each figure marks the 5′ end of the sequence, and the lower left part of each figure marks the 3′ end of the RNA sequence. Mature sequence and its complementary sequence (i.e. the RNA that remains after Drosha and Dicer cleavage) is marked in bold. Positions where mis-matches can be removed or inserted to alter sensitivity to changing Drosha levels are underline.

Positions 5 and/or 9-12 can also be determined based on distance from the Drosha cutting site. For example, 65 angstroms is equal to 25 base pairs (bp) of RNA in a helical (paired) form, or ˜2.6 angstrom per bp RNA. If physical distance in angstroms from a Drosha cutting site is measured along a line following the center of the RNA helix, along the minimum linear path of the shorter strand, the predicted cutting site (Dcp)=0, and the Drosha cutting site (De)=0+e, where e is a continuous random variable between +/−7.8a, nucleotide positions would be: (pos. 5nt)=Dc+(2.6)*5a+r(5) angstroms, (pos. 9nt)=Dc+(2.6)*9+r(9) angstroms, . . . (pos. 12nt)=Dc+(2.6)*12a+r(12) angstroms, where r(x) is the iterative sum of x instances of a continuous random variable between +/−2.6 angstroms divided by the quantity x. If predictions of RNA secondary structure differ from measured structures, position in nucleotide and physical notation should be related as defined. Where multiple subspecies of stable secondary and tertiary structures result from a single sequence of RNA, the relation of position(nt) and physical distance should be calculated for each predicted (or measured) conformation, and modifications applied to either consensus structures, individual structures, or both.

The effects of Drosha expression on RNA based on the number of mis-matches described herein are relative. For example, an RNA with no mis-matches in positions 5 and 9-12 from the Drosha cutting site is least affected by reduced Drosha expression when compared to mRNA with 1, 2, 3, 4 or 5 mis-matches in these positions. RNA with no mis-matches in positions 5 and 9-12 are referred to as “rigid RNAs” herein. Similarly, an RNA with 1 mis-match in positions 5 and 9-12 from the Drosha cutting site is less affected by reduced Drosha expression when compared to mRNA with 2, 3, 4 or 5 mis-matches in these positions. RNA with 1 mis-match in positions 5 and 9-12 are referred to as “semi-rigid RNAs” herein. An RNA with 2 mis-matches in positions 5 and 9-12 from the Drosha cutting site is less affected by reduced Drosha expression when compared to mRNA with 3, 4 or 5 mis-matches in these positions. RNA with 2 mis-match in positions 5 and 9-12 are referred to as “quasi-rigid RNAs” herein. An RNA with 3 mis-matches in positions 5 and 9-12 from the Drosha cutting site is less affected by reduced Drosha expression when compared to mRNA with 4 or 5 mis-matches in these positions. RNA with 3 mis-match in positions 5 and 9-12 are referred to as “mis-matched RNAs” herein. An RNA with 4 mis-matches in positions 5 and 9-12 from the Drosha cutting site is less affected by reduced Drosha expression when compared to mRNA with 5 mis-matches in these positions. RNA with 4 mis-matches in positions 5 and 9-12 are referred to as “highly mis-matched RNAs” herein. An RNA with 5 mis-matches in positions 5 and 9-12 from the Drosha cutting site is most affected by reduced Drosha expression when compared to mRNA with fewer than 5 mis-matches in these positions. RNA with 5 mis-matches in positions 5 and 9-12 are referred to as “fully mis-matched RNAs” herein. Based on the foregoing, low Drosha expression leads to a higher relative percentage of rigid RNAs, followed by semi-rigid RNAs, followed by quasi-rigid RNAs, followed by mis-matched RNAs, followed by highly mis-matched RNAs with the lowest relative percentage of fully-mismatched RNAs. High Drosha expression leads to more equal expression of all RNA types. As used herein, and for convenience only based on the relative nature of the described effects, “unaffected RNAs” can generally include rigid, semi-rigid and quasi-rigid RNAs whereas “affected RNAs” can generally include mis-matched, highly mis-matched and fully-mismatched RNAs.

One of ordinary skill in the art can readily determine whether an RNA is rigid, semi-rigid, quasi-rigid, mis-matched, highly mis-matched or fully mis-matched by referencing available texts and databases.

Exemplary rigid miRNAs include: let7b; let7d; let7f; let7i; miR-1; miR-101; miR-103; miR-105; miR-106a; miR-10a; miR-10b; miR-126*; miR-127; miR-137; miR-138; miR-140; miR-141; miR-142-5p; miR-144; miR-146; miR-153; miR-154; miR-154*; miR-155; miR-17-5p; miR-182*; miR-183; miR-188; miR-189; miR-190; miR-191; miR-192; miR-197; miR-199a*; miR-19a; miR-19b; miR-20; miR-200a; miR-205; miR-206; miR-21; miR-213; miR-22; miR-220; miR-222; miR-224; miR-23b; miR-24; miR-27b; miR-28; miR-299; miR-301; miR-302a; miR-302a*; miR-302b*; miR-302c; miR-302c*; miR-30a-3p; miR-30a-5p; miR-30b; miR-30e-3p; miR-30e-5p; miR-324-5p; miR-326; miR-330; miR-335; miR-337; miR-338; miR-34a; miR-365; miR-368; miR-369; miR-373*; miR-376a; miR-376b; miR-378; miR-380-3p; miR-380-5p; miR-381; miR-382; miR-412; miR-422a; miR-422b; miR-425; miR-429; miR-433; miR-448; miR-449; miR-451; miR-7; miR-9; miR-9*; miR-93; miR-96; and miR-98. Rigid miRNAs can be down-regulated in areas of low Drosha expression by introducing mis-matches in one or more of positions 5 and/or 9-12.

Exemplary semi-rigid miRNAs include: let7a; let7e; let7g; miR-106b; miR-107; miR-122a; miR-124a; miR-126; miR-129; miR-130a; miR-133b; miR-134; miR-135a; miR-139; miR-141; miR-142-3p; miR-143; miR-144; miR-145; miR-147; miR-148a; miR-148b; miR-150; miR-151; miR-152; miR-155; miR-16; miR-17-3p; miR-181a; miR-181b; miR-181c; miR-184; miR-185; miR-186; miR-187; miR-191; miR-192; miR-194; miR-195; miR-196a; miR-198; miR-199a; miR-199b; miR-200a; miR-200c; miR-202; miR-203; miR-204; miR-21; miR-210; miR-215; miR-216; miR-217; miR-218; miR-219; miR-22; miR-224; miR-23a; miR-26a; miR-296; miR-29b; miR-29c; miR-302b; miR-302d; miR-30a-3p; miR-30b; miR-30c; miR-30d; miR-30e-3p; miR-31; miR-32; miR-323; miR-325; miR-328; miR-330; miR-331; miR-338; miR-345; miR-34a; miR-367; miR-371; miR-372; miR-373; miR-374; miR-377; miR-379; miR-380-3p; miR-383; miR-384; miR-410; miR-424; miR-425; miR-431; miR-449; miR-450; miR-452; miR-7; miR-92; miR-93; and miR-96. Semi-rigid miRNAs can be down-regulated in areas of low Drosha expression by introducing mis-matches in one or more of positions 5 and/or 9-12. Semi-rigid miRNAs can be up-regulated in areas of low Drosha expression by removing its mis-match at position 5 and/or 9-12.

Exemplary quasi-rigid miRNAs include: let7c; miR-100; miR-125a; miR-125b; miR-130b; miR-133a; miR-133a; miR-135b; miR-136; miR-148a; miR-149; miR-151; miR-15a; miR-15b; miR-16; miR-18; miR-181a; miR-181c; miR-182; miR-183; miR-196b; miR-19b; miR-200b; miR-200c; miR-202; miR-208; miR-210; miR-211; miR-212; miR-215; miR-216; miR-219; miR-221; miR-23a; miR-26b; miR-27a; miR-301; miR-30d; miR-32; miR-320; miR-324-3p; miR-33; miR-339; miR-342; miR-346; miR-34c; miR-363; miR-370; miR-372; miR-373; miR-423; miR-95; miR-99a; and miR-99b. Quasi-rigid miRNAs can be down-regulated in areas of low Drosha expression by introducing mis-matches in one or more of positions 5 and/or 9-12. Quasi-rigid miRNAs can be up-regulated in areas of low Drosha expression by removing one or more of its mis-matches at position 5 and/or 9-12.

Exemplary mis-matched miRNAs include: miR-128a; miR-128b; miR-132; miR-136; miR-193; miR-200b; miR-214; miR-25; miR-29a; miR-329; miR-340; miR-346; miR-34b; miR-375; and miR-423. Mis-matched miRNAs can be up-regulated in areas of low Drosha expression by removing mis-matches in one or more of positions 5 and/or 9-12. Mis-matched miRNAs can be down-regulated in areas of low Drosha expression by introducing one or more mis-matches at position 5 and/or 9-12.

Exemplary highly-mismatched miRNAs include: miR-340; and miR-342. Highly mis-matched miRNAs can be up-regulated in areas of low Drosha expression by removing mis-matches in one or more of positions 5 and/or 9-12. Highly mis-matched miRNAs can be down-regulated in areas of low Drosha expression by introducing a mis-match at position 5 and/or 9-12.

Fully mis-matched miRNAs can be up-regulated in areas of low Drosha expression by removing one or more mis-matches at positions 5 and/or 9-12.

As used herein in all instances, nucleotide positions, “5 and/or 9-12” means positions 5 and/or 9 and/or 10 and/or 11 and/or 12. Potential combinations for the introduction or removal of mismatches yield the combinations of matched positions versus mis-matched positions as shown in the following Table 3.

TABLE 3
Matched vs. Mis-Matched Position Combinations in
Positions 5 and/or 9-12.
Position 5	Position 9	Position 10	Position 11	Position 12
Mis-match	Mis-match	Mis-match	Mis-match	Mis-match
Match	Mis-match	Mis-match	Mis-match	Mis-match
Mis-match	Match	Mis-match	Mis-match	Mis-match
Mis-match	Mis-match	Match	Mis-match	Mis-match
Mis-match	Mis-match	Mis-match	Match	Mis-match
Mis-match	Mis-match	Mis-match	Mis-match	Match
Match	Match	Mis-match	Mis-match	Mis-match
Match	Mis-match	Match	Mis-match	Mis-match
Match	Mis-match	Mis-match	Match	Mis-match
Match	Mis-match	Mis-match	Mis-match	Match
Mis-match	Match	Match	Mis-match	Mis-match
Mis-match	Match	Mis-match	Match	Mis-match
Mis-match	Match	Mis-match	Mis-match	Match
Mis-match	Mis-match	Match	Match	Mis-match
Mis-match	Mis-match	Match	Mis-match	Match
Mis-match	Mis-match	Mis-match	Match	Match
Match	Match	Match	Mis-match	Mis-match
Match	Match	Mis-match	Match	Mis-match
Match	Match	Mis-match	Mis-match	Match
Match	Mis-match	Match	Match	Mis-match
Match	Mis-match	Match	Mis-match	Match
Match	Mis-match	Mis-match	Match	Match
Mis-match	Match	Match	Match	Mis-match
Mis-match	Match	Mis-match	Match	Match
Mis-match	Match	Match	Mis-match	Match
Mis-match	Mis-match	Match	Match	Match
Match	Match	Match	Match	Mis-match
Match	Match	Match	Mis-match	Match
Match	Match	Mis-match	Match	Match
Match	Mis-match	Match	Match	Match
Mis-match	Match	Match	Match	Match
Match	Match	Match	Match	Match

Further, as used herein, “miR” refers to both hairpin structures and/or mature miRNA.

Drosha levels vary between tissues and throughout cell development. For example, the brain expresses higher levels of Drosha than the liver. Further, Drosha levels decrease over the course of T-cell development and as stem cells differentiate into neurons. These differences support the hypothesis that cells could selectively regulate RNA expression by altering Drosha expression level. This is a novel mechanism which may be utilized while designing artificial RNAs either for general stability, or to control expression levels throughout differentiation when Drosha levels change, as well as fine tuning differential expression in different tissue types.

High versus low Drosha expression can be determined or quantified by various methods. For example, in one embodiment, high versus low Drosha expression is a relative determination from samples taken from the same subject. When determined using an intra-subject comparison, high versus low can be compared from the same tissue at different time points or can be compared at the same time using a reference tissue, such as T-cells, liver or brain. Additionally, population reference standards can be created by averaging levels of Drosha expression across a group of subjects at a given time during development and for a particular tissue type. A particular subject's Drosha expression could then be appropriately compared to the population reference to determine if the particular subject's level of Drosha expression is high or low. Another option is to define Drosha expression levels according to fragments per kilobase of exon per million fragments mapped (FPKM). See, for example, the human protein atlas:http://www.proteinatlas.org/ENSG00000113360/tissue. In this method, Drosha levels of ≧16 FPKM are considered high and Drosha levels <16 FPKM are considered low. Averages can be generated depending on the protein quantification method used. Within this context, the liver exhibits low Drosha expression (9 FPKM) and the brain (cerebral cortex) exhibits high Drosha expression (22 FPKM).

I. Drosha Regulation to Alter Cellular RNA Profiles

The current disclosure provides a mechanism to alter cellular RNA profiles by up- or down-regulating Drosha expression. Down-regulating Drosha expression results in a cellular RNA profile with a higher percentage of unaffected RNAs than if Drosha expression had not been down-regulated. If Drosha expression is naturally low in a cell type or period during development, up-regulating Drosha expression results in a cellular miRNA profiled with a higher percentage of affected RNA than if Drosha expression had not been up-regulated.

As used herein, “down-regulation” of Drosha means a reduction in the presence or activity of the Drosha protein. The reduction in the presence or activity lessens the physiological impact of Drosha within a cell. The down-regulation can occur due to translation of an incomplete Drosha protein sequence; incorrect folding of Drosha; or enhanced degradation of Drosha once formed. Down-regulation of Drosha can also occur due to elimination of the Drosha gene's expression (i.e. gene knockout); insertion of a nucleotide or polynucleotide molecule into the native Drosha gene sequence whereby the expression of the mutated gene is down-regulated (either partially or completely); insertion of a foreign set of base pairs in a Drosha coding region; deletion of any portion of the Drosha gene; reduced transcription of the Drosha gene; incomplete transcription of the Drosha gene; and/or interference with transcription or translation of the Drosha gene or Drosha mRNA.

An up-regulation of Drosha's activity may occur through one or more of increased presence of Drosha or increased potency of Drosha. An increased presence of Drosha can occur through its administration as a protein therapeutic, through genetic modifications that increase its expression and/or by its reduced degradation following administration or formation. Increased expression of Drosha can occur by increasing the copy number of the Drosha gene. Alternatively, a strong and/or inducible promoter may be used to direct the expression of the Drosha gene, the gene being expressed either as a transient expression vehicle or homologously or heterologously incorporated into the genome. In another embodiment, the promoter, regulatory region and/or the ribosome binding site upstream of the Drosha gene can be altered to achieve the over-expression. The expression may also be enhanced by increasing the relative half-life of Drosha mRNA. Increased potency of Drosha can occur through modifying the naturally occurring Drosha sequence to show enhanced cleavage of pri-miRNA.

As is understood by one of ordinary skill in the art, “down-regulation” and “up-regulation” can be measured against a relevant control condition.

II. miRNA Regulation Based on High or Low Drosha Expression

According to the present disclosure, miRNA can also be up- or down-regulated based on naturally occurring Drosha expression levels. For example, when Drosha expression levels are low, it may be desirable to (i) up-regulate affected RNA as these RNA naturally would be down-regulated in tissues with low Drosha expression and/or (ii) down-regulate unaffected RNA as these RNA naturally would be up-regulated in tissues with low Drosha expression. Alternatively, in areas with high Drosha expression, it may be desirable to (i) down-regulate affected RNA as these RNA naturally would be up-regulated in tissues with high Drosha expression and/or (ii) up-regulate unaffected miRNA as these miRNA naturally would be down-regulated as a percentage when compared to affected miRNA in tissues with high Drosha expression.

As used herein, “down-regulation” of RNA means a reduction in the presence or activity of an RNA. The reduction in the presence or activity lessens the physiological impact of the RNA within a cell. The down-regulation can occur due to reduced or incomplete transcription of an RNA gene sequence; enhanced degradation of RNA once it is formed; elimination of the RNA gene's expression (i.e. gene knockout); insertion of a nucleotide or polynucleotide molecule into the native gene sequence whereby expression of the mutated gene is down-regulated (either partially or completely); insertion of a foreign set of base pairs in a coding region; and/or deletion of any portion of the RNA gene.

An up-regulation of an RNA's activity may occur through one or more of increased presence or increased potency of the RNA. An increased presence of RNA can occur through its administration as a therapeutic, through genetic modifications that increase its expression and/or by its reduced degradation following administration or formation. Increased expression of RNA can occur by increasing the copy number of the RNA gene. Alternatively, a strong and/or inducible promoter may be used to direct the expression of the RNA gene, the gene being expressed either as a transient expression vehicle or homologously or heterologously incorporated into the genome. In another embodiment, the promoter, regulatory region and/or the ribosome binding site upstream of the RNA gene can be altered to achieve the over-expression. The expression may also be enhanced by increasing the relative half-life of RNA. Increased potency of miRNA can occur through modifying the naturally occurring sequence to show enhanced mRNA binding.

III. Artificial RNA Design to Provide Enhanced or Repressed RNA Processing

Based on the teachings of the present disclosure, RNA, including miRNA, can be designed to enhance or repress processing of the endogenous form of the RNA by removing or introducing mis-matches into nt positions 5 and/or 9-12 from the Drosha cutting site. Mis-matches are removed to enhance processing by making the RNA less susceptible to down-regulated Drosha expression. Mis-matches are introduced to repress processing by making RNA more susceptible to down-regulated Drosha expression.

Within the context of the designed artificial miRNAs, the term “miRNA” refers to any non-endogenous microRNA molecule that can be involved in RNA-based gene regulation. Accordingly, “miRNA” refers to any type of RNA capable of modulating the productive utilization of mRNA. The term “mRNA” refers to a nucleic acid transcribed from a gene from which a polypeptide is translated, and may include non-translated regions such as a 5′UTR and/or a 3′UTR. An miRNA can include a nucleotide sequence that is completely or partially complementary to any sequence of an mRNA molecule, including translated regions, the 5′UTR, the 3′UTR, and sequences that include both a translated region and a portion of either 5′UTR or 3′UTR. An miRNA may also comprise a nucleotide sequence that is complementary to a region of an mRNA molecule spanning the start codon or the stop codon.

Artificial miRNA can be designed based on any endogenous or naturally-occurring miRNA. Exemplary miRNA for use in the context of the current disclosure include any human, animal, or plant miRNA for various medicinal, veterinary, research, or agricultural purposes. For example, the following human miRNAs could be used: let-7a-1 (SEQ ID NO:1); let-7a-2 (SEQ ID NO:2); let-7a-3 (SEQ ID NO:3); let-7b (SEQ ID NO:4); let-7c (SEQ ID NO:5); let-7d (SEQ ID NO:6); let-7e (SEQ ID NO:7); let-7f-1 (SEQ ID NO:8); let-7f-2 (SEQ ID NO:9); let-7g (SEQ ID NO:10); let-7i (SEQ ID NO:11); miR-1-2 (SEQ ID NO:27); miR-1-1 (SEQ ID NO:26); miR-7-3 (SEQ ID NO:279); miR-7-2 (SEQ ID NO:278); miR-7-1 (SEQ ID NO:277); miR-9-3 (SEQ ID NO:286); miR-9-2 (SEQ ID NO:281); miR-9-1 (SEQ ID NO:280); miR-10a (SEQ ID NO:24); miR-10b (SEQ ID NO:25); miR-15a (SEQ ID NO:77); miR-15b (SEQ ID NO:78); miR-16-2 (SEQ ID NO:80); miR-16-1 (SEQ ID NO:79); miR-17 (SEQ ID NO:81); miR-18a (SEQ ID NO:95); miR-18b (SEQ ID NO:96); miR-19a (SEQ ID NO:114); miR-19b-1 (SEQ ID NO:115); miR-19b-2 (SEQ ID NO:116); miR-20a (SEQ ID NO:128); miR-20b (SEQ ID NO:129); miR-21 (SEQ ID NO:130); miR-22 (SEQ ID NO:144); miR-23a (SEQ ID NO:149); miR-23b (SEQ ID NO:150); miR-23c (SEQ ID NO:151); miR-24-2 (SEQ ID NO:153); miR-24-1 (SEQ ID NO:152); miR-25 (SEQ ID NO:154); miR-26a-1 (SEQ ID NO:155); miR-26a-2 (SEQ ID NO:156); miR-26b (SEQ ID NO:157); miR-27a (SEQ ID NO:158); miR-27b (SEQ ID NO:159); miR-28 (SEQ ID NO:160); miR-29a (SEQ ID NO:165); miR-29b-1 (SEQ ID NO:166); miR-29b-2 (SEQ ID NO:167); miR-29c (SEQ ID NO:168); miR-30a (SEQ ID NO:178); miR-30b (SEQ ID NO:179); miR-30c-1 (SEQ ID NO:180); miR-30c-2 (SEQ ID NO:181); miR-30d (SEQ ID NO:182); miR-30e (SEQ ID NO:183); miR-31 (SEQ ID NO:184); miR-32 (SEQ ID NO:185); miR-33a (SEQ ID NO:208); miR-33b (SEQ ID NO:209); miR-34a (SEQ ID NO:214); miR-34b (SEQ ID NO:215); miR-34c (SEQ ID NO:216); miR-92a-1 (SEQ ID NO:282); miR-92a-2 (SEQ ID NO:283); miR-92b (SEQ ID NO:284); miR-93 (SEQ ID NO:285); miR-95 (SEQ ID NO:287); miR-96 (SEQ ID NO:288); miR-98 (SEQ ID NO:289); miR-99a (SEQ ID NO:290); miR-99b (SEQ ID NO:291); miR-100 (SEQ ID NO:12); miR-101-2 (SEQ ID NO:14); miR-101-1 (SEQ ID NO:13); miR-103a-1 (SEQ ID NO:15); miR-103a-2 (SEQ ID NO:16); miR-103b-1 (SEQ ID NO:17); miR-103b-2 (SEQ ID NO:18); miR-105-2 (SEQ ID NO:20); miR-105-1 (SEQ ID NO:19); miR-106a (SEQ ID NO:21); miR-106b (SEQ ID NO:22); miR-107 (SEQ ID NO:23); miR-122 (SEQ ID NO:28); miR-124-3 (SEQ ID NO:31); miR-124-2 (SEQ ID NO:30); miR-124-1 (SEQ ID NO:29); miR-125a (SEQ ID NO:32); miR-125b-1 (SEQ ID NO:33); miR-125b-2 (SEQ ID NO:34); miR-126 (SEQ ID NO:35); miR-127 (SEQ ID NO:36); miR-128-2 (SEQ ID NO:38); miR-128-1 (SEQ ID NO:37); miR-129-2 (SEQ ID NO:40); miR-129-1 (SEQ ID NO:39); miR-130a (SEQ ID NO:41); miR-130b (SEQ ID NO:42); miR-132 (SEQ ID NO:43); miR-133a-1 (SEQ ID NO:44); miR-133a-2 (SEQ ID NO:45); miR-133b (SEQ ID NO:46); miR-134 (SEQ ID NO:47); miR-135a-1 (SEQ ID NO:48); miR-135a-2 (SEQ ID NO:49); miR-135b (SEQ ID NO:50); miR-136 (SEQ ID NO:51); miR-137 (SEQ ID NO:52); miR-138-2 (SEQ ID NO:54); miR-138-1 (SEQ ID NO:53); miR-139 (SEQ ID NO:55); miR-140 (SEQ ID NO:56); miR-141 (SEQ ID NO:57); miR-142 (SEQ ID NO:58); miR-143 (SEQ ID NO:59); miR-144 (SEQ ID NO:60); miR-145 (SEQ ID NO:61); miR-146a (SEQ ID NO:62); miR-146b (SEQ ID NO:63); miR-147a (SEQ ID NO:64); miR-147b (SEQ ID NO:65); miR-148a (SEQ ID NO:66); miR-148b (SEQ ID NO:67); miR-149 (SEQ ID NO:68); miR-150 (SEQ ID NO:69); miR-151a (SEQ ID NO:70); miR-151b (SEQ ID NO:71); miR-152 (SEQ ID NO:72); miR-153-2 (SEQ ID NO:74); miR-153-1 (SEQ ID NO:73); miR-154 (SEQ ID NO:75); miR-155 (SEQ ID NO:76); miR-181a-1 (SEQ ID NO:82); miR-181a-2 (SEQ ID NO:83); miR-181b-1 (SEQ ID NO:84); miR-181b-2 (SEQ ID NO:85); miR-181c (SEQ ID NO:86); miR-181d (SEQ ID NO:87); miR-182 (SEQ ID NO:88); miR-183 (SEQ ID NO:89); miR-184 (SEQ ID NO:90); miR-185 (SEQ ID NO:91); miR-186 (SEQ ID NO:92); miR-187 (SEQ ID NO:93); miR-188 (SEQ ID NO:94); miR-190a (SEQ ID NO:97); miR-190b (SEQ ID NO:98); miR-191 (SEQ ID NO:99); miR-192 (SEQ ID NO:100); miR-193a (SEQ ID NO:101); miR-193b (SEQ ID NO:102); miR-194-2 (SEQ ID NO:104); miR-194-1 (SEQ ID NO:103); miR-195 (SEQ ID NO:105); miR-196a-1 (SEQ ID NO:106); miR-196a-2 (SEQ ID NO:107); miR-196b (SEQ ID NO:108); miR-197 (SEQ ID NO:109); miR-198 (SEQ ID NO:110); miR-199a-1 (SEQ ID NO:111); miR-199a-2 (SEQ ID NO:112); miR-199b (SEQ ID NO:113); miR-200a (SEQ ID NO:117); miR-200b (SEQ ID NO:118); miR-200c (SEQ ID NO:119); miR-202 (SEQ ID NO:120); miR-203a (SEQ ID NO:121); miR-203b (SEQ ID NO:122); miR-204 (SEQ ID NO:123); miR-205 (SEQ ID NO:124); miR-206 (SEQ ID NO:125); miR-208a (SEQ ID NO:126); miR-208b (SEQ ID NO:127); miR-210 (SEQ ID NO:131); miR-211 (SEQ ID NO:132); miR-212 (SEQ ID NO:133); miR-214 (SEQ ID NO:134); miR-215 (SEQ ID NO:135); miR-216a (SEQ ID NO:136); miR-216b (SEQ ID NO:137); miR-217 (SEQ ID NO:138); miR-218-2 (SEQ ID NO:140); miR-218-1 (SEQ ID NO:139); miR-219a-1 (SEQ ID NO:141); miR-219a-2 (SEQ ID NO:142); miR-219b (SEQ ID NO:143); miR-221 (SEQ ID NO:145); miR-222 (SEQ ID NO:146); miR-223 (SEQ ID NO:147); miR-224 (SEQ ID NO:148); miR-296 (SEQ ID NO:161); miR-297 (SEQ ID NO:162); miR-298 (SEQ ID NO:163); miR-299 (SEQ ID NO:164); miR-300 (SEQ ID NO:169); miR-301a (SEQ ID NO:170); miR-301a (SEQ ID NO:171); miR-302a (SEQ ID NO:172); miR-302b (SEQ ID NO:173); miR-302c (SEQ ID NO:174); miR-302d (SEQ ID NO:175); miR-302e (SEQ ID NO:176); miR-302f (SEQ ID NO:177); miR-320a (SEQ ID NO:186); miR-320b-1 (SEQ ID NO:187); miR-320b-2 (SEQ ID NO:188); miR-320c-1 (SEQ ID NO:189); miR-320c-2 (SEQ ID NO:190); miR-320d-1 (SEQ ID NO:191); miR-320d-2 (SEQ ID NO:192); miR-320e (SEQ ID NO:193); miR-323a (SEQ ID NO:194); miR-323b (SEQ ID NO:195); miR-324 (SEQ ID NO:196); miR-325 (SEQ ID NO:197); miR-326 (SEQ ID NO:198); miR-328 (SEQ ID NO:199); miR-329-2 (SEQ ID NO:201); miR-329-1 (SEQ ID NO:200); miR-330 (SEQ ID NO:202); miR-331 (SEQ ID NO:203); miR-335 (SEQ ID NO:204); miR-337 (SEQ ID NO:205); miR-338 (SEQ ID NO:206); miR-339 (SEQ ID NO:207); miR-340 (SEQ ID NO:210); miR-342 (SEQ ID NO:211); miR-345 (SEQ ID NO:212); miR-346 (SEQ ID NO:213); miR-361 (SEQ ID NO:217); miR-362 (SEQ ID NO:218); miR-363 (SEQ ID NO:219); miR-365a (SEQ ID NO:220); miR-365b (SEQ ID NO:221); miR-367 (SEQ ID NO:222); miR-369 (SEQ ID NO:223); miR-370 (SEQ ID NO:224); miR-371a (SEQ ID NO:225); miR-371b (SEQ ID NO:226); miR-372 (SEQ ID NO:227); miR-373 (SEQ ID NO:228); miR-374a (SEQ ID NO:229); miR-374b (SEQ ID NO:230); miR-374c (SEQ ID NO:231); miR-375 (SEQ ID NO:232); miR-376a-1 (SEQ ID NO:233); miR-376a-2 (SEQ ID NO:234); miR-376b (SEQ ID NO:235); miR-376c (SEQ ID NO:236); miR-377 (SEQ ID NO:237); miR-378a (SEQ ID NO:238); miR-378b (SEQ ID NO:239); miR-378c (SEQ ID NO:240); miR-378d-1 (SEQ ID NO:241); miR-378d-2 (SEQ ID NO:242); miR-378e (SEQ ID NO:243); miR-378f (SEQ ID NO:244); miR-378g (SEQ ID NO:245); miR-378h (SEQ ID NO:246); miR-378i (SEQ ID NO:247); miR-378j (SEQ ID NO:248); miR-379 (SEQ ID NO:249); miR-380 (SEQ ID NO:250); miR-381 (SEQ ID NO:251); miR-382 (SEQ ID NO:252); miR-383 (SEQ ID NO:253); miR-384 (SEQ ID NO:254); miR-409 (SEQ ID NO:255); miR-410 (SEQ ID NO:256); miR-411 (SEQ ID NO:257); miR-412 (SEQ ID NO:258); miR-421 (SEQ ID NO:259); miR-422a (SEQ ID NO:260); miR-423 (SEQ ID NO:261); miR-424 (SEQ ID NO:262); miR-425 (SEQ ID NO:263); miR-429 (SEQ ID NO:264); miR-431 (SEQ ID NO:265); miR-432 (SEQ ID NO:266); miR-433 (SEQ ID NO:267); miR-448 (SEQ ID NO:268); miR-449a (SEQ ID NO:269); miR-449b (SEQ ID NO:270); miR-449c (SEQ ID NO:271); miR-450a-1 (SEQ ID NO:272); miR-450a-2 (SEQ ID NO:273); miR-450b (SEQ ID NO:274); miR-451a (SEQ ID NO:275); miR-451b (SEQ ID NO:276); miR-452 (SEQ ID NO:292); miR-454 (SEQ ID NO:293); miR-455 (SEQ ID NO:294); miR-466 (SEQ ID NO:295); miR-483 (SEQ ID NO:296); miR-484 (SEQ ID NO:297); miR-485 (SEQ ID NO:298); miR-486-2 (SEQ ID NO:300); miR-486 (SEQ ID NO:299); miR-487a (SEQ ID NO:301); miR-487b (SEQ ID NO:302); miR-488 (SEQ ID NO:303); miR-489 (SEQ ID NO:304); miR-490 (SEQ ID NO:305); miR-491 (SEQ ID NO:306); miR-492 (SEQ ID NO:307); miR-493 (SEQ ID NO:308); miR-494 (SEQ ID NO:309); miR-495 (SEQ ID NO:310); miR-496 (SEQ ID NO:311); miR-497 (SEQ ID NO:312); miR-498 (SEQ ID NO:313); miR-499a (SEQ ID NO:314); miR-499b (SEQ ID NO:315); miR-500a (SEQ ID NO:316); miR-500b (SEQ ID NO:317); miR-501 (SEQ ID NO:318); miR-502 (SEQ ID NO:319); miR-503 (SEQ ID NO:320); miR-504 (SEQ ID NO:321); miR-505 (SEQ ID NO:322); miR-506 (SEQ ID NO:323); miR-507 (SEQ ID NO:324); miR-508 (SEQ ID NO:325); miR-509-3 (SEQ ID NO:328); miR-509-2 (SEQ ID NO:327); miR-509-1 (SEQ ID NO:326); miR-510 (SEQ ID NO:329); miR-511 (SEQ ID NO:330); miR-512-2 (SEQ ID NO:332); miR-512-1 (SEQ ID NO:331); miR-513a-1 (SEQ ID NO:333); miR-513a-2 (SEQ ID NO:334); miR-513b (SEQ ID NO:335); miR-513c (SEQ ID NO:336); miR-514a-1 (SEQ ID NO:337); miR-514a-2 (SEQ ID NO:338); miR-514a-3 (SEQ ID NO:339); miR-514b (SEQ ID NO:340); miR-515-2 (SEQ ID NO:342); miR-515-1 (SEQ ID NO:341); miR-516a-1 (SEQ ID NO:343); miR-516a-2 (SEQ ID NO:344); miR-516b-1 (SEQ ID NO:345); miR-516b-2 (SEQ ID NO:346); miR-517a (SEQ ID NO:347); miR-517b (SEQ ID NO:348); miR-517c (SEQ ID NO:349); miR-518a-1 (SEQ ID NO:350); miR-518a-2 (SEQ ID NO:351); miR-518b (SEQ ID NO:352); miR-518c (SEQ ID NO:353); miR-518d (SEQ ID NO:354); miR-518e (SEQ ID NO:355); miR-518f (SEQ ID NO:356); miR-519a-1 (SEQ ID NO:357); miR-519a-2 (SEQ ID NO:358); miR-519b (SEQ ID NO:359); miR-519c (SEQ ID NO:360); miR-519d (SEQ ID NO:361); miR-519e (SEQ ID NO:362); miR-520a (SEQ ID NO:363); miR-520b (SEQ ID NO:364); miR-520c (SEQ ID NO:365); miR-520d (SEQ ID NO:366); miR-520e (SEQ ID NO:367); miR-520f (SEQ ID NO:368); miR-520g (SEQ ID NO:369); miR-520h (SEQ ID NO:370); miR-521-2 (SEQ ID NO:372); miR-521-1 (SEQ ID NO:371); miR-522 (SEQ ID NO:373); miR-523 (SEQ ID NO:374); miR-524 (SEQ ID NO:375); miR-525 (SEQ ID NO:376); miR-526a-1 (SEQ ID NO:377); miR-526a-2 (SEQ ID NO:378); miR-526b (SEQ ID NO:379); miR-527 (SEQ ID NO:380); miR-532 (SEQ ID NO:381); miR-539 (SEQ ID NO:382); miR-541 (SEQ ID NO:383); miR-542 (SEQ ID NO:384); miR-543 (SEQ ID NO:385); miR-544a (SEQ ID NO:386); miR-544b (SEQ ID NO:387); miR-545 (SEQ ID NO:388); miR-548a-1 (SEQ ID NO:389); miR-548a-2 (SEQ ID NO:390); miR-548a-3 (SEQ ID NO:391); miR-548aa-1 (SEQ ID NO:392); miR-548aa-2 (SEQ ID NO:393); miR-548ab (SEQ ID NO:394); miR-548ac (SEQ ID NO:395); miR-548ad (SEQ ID NO:396); miR-548ae-1 (SEQ ID NO:397); miR-548ae-2 (SEQ ID NO:398); miR-548ag-1 (SEQ ID NO:399); miR-548ag-2 (SEQ ID NO:400); miR-548ah (SEQ ID NO:401); miR-548ai (SEQ ID NO:402); miR-548aj-1 (SEQ ID NO:403); miR-548aj-2 (SEQ ID NO:404); miR-548ak (SEQ ID NO:405); miR-548al (SEQ ID NO:406); miR-548am (SEQ ID NO:407); miR-548an (SEQ ID NO:408); miR-548ao (SEQ ID NO:409); miR-548ap (SEQ ID NO:410); miR-548aq (SEQ ID NO:411); miR-548ar (SEQ ID NO:412); miR-548as (SEQ ID NO:413); miR-548at (SEQ ID NO:414); miR-548au (SEQ ID NO:415); miR-548av (SEQ ID NO:416); miR-548aw (SEQ ID NO:417); miR-548ax (SEQ ID NO:418); miR-548ay (SEQ ID NO:419); miR-548az (SEQ ID NO:420); miR-548b (SEQ ID NO:421); miR-548ba (SEQ ID NO:422); miR-548c (SEQ ID NO:423); miR-548d-1 (SEQ ID NO:424); miR-548d-2 (SEQ ID NO:425); miR-548e (SEQ ID NO:426); miR-548f-1 (SEQ ID NO:427); miR-548f-2 (SEQ ID NO:428); miR-548f-3 (SEQ ID NO:429); miR-548f-4 (SEQ ID NO:430); miR-548f-5 (SEQ ID NO:431); miR-548g (SEQ ID NO:432); miR-548h-1 (SEQ ID NO:433); miR-548h-2 (SEQ ID NO:434); miR-548h-3 (SEQ ID NO:435); miR-548h-4 (SEQ ID NO:436); miR-548h-5 (SEQ ID NO:437); miR-548i-1 (SEQ ID NO:438); miR-548i-2 (SEQ ID NO:439); miR-548i-3 (SEQ ID NO:440); miR-548i-4 (SEQ ID NO:441); miR-548j (SEQ ID NO:442); miR-548k (SEQ ID NO:443); miR-548l (SEQ ID NO:444); miR-548m (SEQ ID NO:445); miR-548n (SEQ ID NO:446); miR-548o (SEQ ID NO:447); miR-548o-2 (SEQ ID NO:448); miR-548p (SEQ ID NO:449); miR-548q (SEQ ID NO:450); miR-548s (SEQ ID NO:451); miR-548t (SEQ ID NO:452); miR-548u (SEQ ID NO:453); miR-548v (SEQ ID NO:454); miR-548w (SEQ ID NO:455); miR-548x (SEQ ID NO:456); miR-548x-2 (SEQ ID NO:457); miR-548y (SEQ ID NO:458); miR-548z (SEQ ID NO:459); miR-549a (SEQ ID NO:460); miR-550a-1 (SEQ ID NO:461); miR-550a-2 (SEQ ID NO:462); miR-550a-3 (SEQ ID NO:463); miR-550b-1 (SEQ ID NO:464); miR-550b-2 (SEQ ID NO:465); miR-551a (SEQ ID NO:466); miR-551b (SEQ ID NO:467); miR-552 (SEQ ID NO:468); miR-553 (SEQ ID NO:469); miR-554 (SEQ ID NO:470); miR-555 (SEQ ID NO:471); miR-556 (SEQ ID NO:472); miR-557 (SEQ ID NO:473); miR-558 (SEQ ID NO:474); miR-559 (SEQ ID NO:475); miR-561 (SEQ ID NO:476); miR-562 (SEQ ID NO:477); miR-563 (SEQ ID NO:478); miR-564 (SEQ ID NO:479); miR-566 (SEQ ID NO:480); miR-567 (SEQ ID NO:481); miR-568 (SEQ ID NO:482); miR-569 (SEQ ID NO:483); miR-570 (SEQ ID NO:484); miR-571 (SEQ ID NO:485); miR-572 (SEQ ID NO:486); miR-573 (SEQ ID NO:487); miR-574 (SEQ ID NO:488); miR-575 (SEQ ID NO:489); miR-576 (SEQ ID NO:490); miR-577 (SEQ ID NO:491); miR-578 (SEQ ID NO:492); miR-579 (SEQ ID NO:493); miR-580 (SEQ ID NO:494); miR-581 (SEQ ID NO:495); miR-582 (SEQ ID NO:496); miR-583 (SEQ ID NO:497); miR-584 (SEQ ID NO:498); miR-585 (SEQ ID NO:499); miR-586 (SEQ ID NO:500); miR-587 (SEQ ID NO:501); miR-588 (SEQ ID NO:502); miR-589 (SEQ ID NO:503); miR-590 (SEQ ID NO:504); miR-591 (SEQ ID NO:505); miR-592 (SEQ ID NO:506); miR-593 (SEQ ID NO:507); miR-595 (SEQ ID NO:508); miR-596 (SEQ ID NO:509); miR-597 (SEQ ID NO:510); miR-598 (SEQ ID NO:511); miR-599 (SEQ ID NO:512); miR-600 (SEQ ID NO:513); miR-601 (SEQ ID NO:514); miR-602 (SEQ ID NO:515); miR-603 (SEQ ID NO:516); miR-604 (SEQ ID NO:517); miR-605 (SEQ ID NO:518); miR-606 (SEQ ID NO:519); miR-607 (SEQ ID NO:520); miR-608 (SEQ ID NO:521); miR-609 (SEQ ID NO:522); miR-610 (SEQ ID NO:523); miR-611 (SEQ ID NO:524); miR-612 (SEQ ID NO:525); miR-613 (SEQ ID NO:526); miR-614 (SEQ ID NO:527); miR-615 (SEQ ID NO:528); miR-616 (SEQ ID NO:529); miR-617 (SEQ ID NO:530); miR-618 (SEQ ID NO:531); miR-619 (SEQ ID NO:532); miR-620 (SEQ ID NO:533); miR-621 (SEQ ID NO:534); miR-622 (SEQ ID NO:535); miR-623 (SEQ ID NO:536); miR-624 (SEQ ID NO:537); miR-625 (SEQ ID NO:538); miR-626 (SEQ ID NO:539); miR-627 (SEQ ID NO:540); miR-628 (SEQ ID NO:541); miR-629 (SEQ ID NO:542); miR-630 (SEQ ID NO:543); miR-631 (SEQ ID NO:544); miR-632 (SEQ ID NO:545); miR-633 (SEQ ID NO:546); miR-634 (SEQ ID NO:547); miR-635 (SEQ ID NO:548); miR-636 (SEQ ID NO:549); miR-637 (SEQ ID NO:550); miR-638 (SEQ ID NO:551); miR-639 (SEQ ID NO:552); miR-640 (SEQ ID NO:553); miR-641 (SEQ ID NO:554); miR-642a (SEQ ID NO:555); miR-642b (SEQ ID NO:556); miR-643 (SEQ ID NO:557); miR-644a (SEQ ID NO:558); miR-645 (SEQ ID NO:559); miR-646 (SEQ ID NO:560); miR-647 (SEQ ID NO:561); miR-648 (SEQ ID NO:562); miR-649 (SEQ ID NO:563); miR-650 (SEQ ID NO:564); miR-651 (SEQ ID NO:565); miR-652 (SEQ ID NO:566); miR-653 (SEQ ID NO:567); miR-654 (SEQ ID NO:568); miR-655 (SEQ ID NO:569); miR-656 (SEQ ID NO:570); miR-657 (SEQ ID NO:571); miR-658 (SEQ ID NO:572); miR-659 (SEQ ID NO:573); miR-660 (SEQ ID NO:574); miR-661 (SEQ ID NO:575); miR-662 (SEQ ID NO:576); miR-663a (SEQ ID NO:577); miR-663b (SEQ ID NO:578); miR-664a (SEQ ID NO:579); miR-664b (SEQ ID NO:580); miR-665 (SEQ ID NO:581); miR-668 (SEQ ID NO:582); miR-670 (SEQ ID NO:583); miR-671 (SEQ ID NO:584); miR-675 (SEQ ID NO:585); miR-676 (SEQ ID NO:586); miR-708 (SEQ ID NO:587); miR-711 (SEQ ID NO:588); miR-718 (SEQ ID NO:589); miR-744 (SEQ ID NO:590); miR-758 (SEQ ID NO:591); miR-759 (SEQ ID NO:592); miR-760 (SEQ ID NO:593); miR-761 (SEQ ID NO:594); miR-762 (SEQ ID NO:595); miR-764 (SEQ ID NO:596); miR-765 (SEQ ID NO:597); miR-766 (SEQ ID NO:598); miR-767 (SEQ ID NO:599); miR-769 (SEQ ID NO:600); miR-770 (SEQ ID NO:601); miR-802 (SEQ ID NO:602); miR-873 (SEQ ID NO:603); miR-874 (SEQ ID NO:604); miR-875 (SEQ ID NO:605); miR-876 (SEQ ID NO:606); miR-877 (SEQ ID NO:607); miR-885 (SEQ ID NO:608); miR-887 (SEQ ID NO:609); miR-888 (SEQ ID NO:610); miR-889 (SEQ ID NO:611); miR-890 (SEQ ID NO:612); miR-891a (SEQ ID NO:613); miR-891b (SEQ ID NO:614); miR-892a (SEQ ID NO:615); miR-892b (SEQ ID NO:616); miR-892c (SEQ ID NO:617); miR-920 (SEQ ID NO:618); miR-921 (SEQ ID NO:619); miR-922 (SEQ ID NO:620); miR-924 (SEQ ID NO:621); miR-933 (SEQ ID NO:622); miR-934 (SEQ ID NO:623); miR-935 (SEQ ID NO:624); miR-936 (SEQ ID NO:625); miR-937 (SEQ ID NO:626); miR-938 (SEQ ID NO:627); miR-939 (SEQ ID NO:628); miR-940 (SEQ ID NO:629); miR-941-4 (SEQ ID NO:633); miR-941-3 (SEQ ID NO:632); miR-941-2 (SEQ ID NO:631); miR-941-1 (SEQ ID NO:630); miR-942 (SEQ ID NO:634); miR-943 (SEQ ID NO:635); miR-944 (SEQ ID NO:636); miR-1178 (SEQ ID NO:637); miR-1179 (SEQ ID NO:638); miR-1180 (SEQ ID NO:639); miR-1181 (SEQ ID NO:640); miR-1182 (SEQ ID NO:641); miR-1183 (SEQ ID NO:642); miR-1184-3 (SEQ ID NO:645); miR-1184-2 (SEQ ID NO:644); miR-1184-1 (SEQ ID NO:643); miR-1185-2 (SEQ ID NO:647); miR-1185-1 (SEQ ID NO:646); miR-1193 (SEQ ID NO:648); miR-1197 (SEQ ID NO:649); miR-1199 (SEQ ID NO:650); miR-1200 (SEQ ID NO:651); miR-1202 (SEQ ID NO:652); miR-1203 (SEQ ID NO:653); miR-1204 (SEQ ID NO:654); miR-1205 (SEQ ID NO:655); miR-1206 (SEQ ID NO:656); miR-1207 (SEQ ID NO:657); miR-1208 (SEQ ID NO:658); miR-1224 (SEQ ID NO:659); miR-1225 (SEQ ID NO:660); miR-1226 (SEQ ID NO:661); miR-1227 (SEQ ID NO:662); miR-1228 (SEQ ID NO:663); miR-1229 (SEQ ID NO:664); miR-1231 (SEQ ID NO:665); miR-1233-2 (SEQ ID NO:667); miR-1233-1 (SEQ ID NO:666); miR-1234 (SEQ ID NO:668); miR-1236 (SEQ ID NO:669); miR-1237 (SEQ ID NO:670); miR-1238 (SEQ ID NO:671); miR-1243 (SEQ ID NO:672); miR-1244-3 (SEQ ID NO:675); miR-1244-2 (SEQ ID NO:674); miR-1244-1 (SEQ ID NO:673); miR-1245a (SEQ ID NO:676); miR-1245b (SEQ ID NO:677); miR-1246 (SEQ ID NO:678); miR-1247 (SEQ ID NO:679); miR-1248 (SEQ ID NO:680); miR-1249 (SEQ ID NO:681); miR-1250 (SEQ ID NO:682); miR-1251 (SEQ ID NO:683); miR-1252 (SEQ ID NO:684); miR-1253 (SEQ ID NO:685); miR-1254-2 (SEQ ID NO:687); miR-1254-1 (SEQ ID NO:686); miR-1255a (SEQ ID NO:688); miR-1255b-1 (SEQ ID NO:689); miR-1255b-2 (SEQ ID NO:690); miR-1256 (SEQ ID NO:691); miR-1257 (SEQ ID NO:692); miR-1258 (SEQ ID NO:693); miR-1260a (SEQ ID NO:694); miR-1260b (SEQ ID NO:695); miR-1261 (SEQ ID NO:696); miR-1262 (SEQ ID NO:697); miR-1263 (SEQ ID NO:698); miR-1264 (SEQ ID NO:699); miR-1265 (SEQ ID NO:700); miR-1266 (SEQ ID NO:701); miR-1267 (SEQ ID NO:702); miR-1268a (SEQ ID NO:703); miR-1268b (SEQ ID NO:704); miR-1269a (SEQ ID NO:705); miR-1269b (SEQ ID NO:706); miR-1270-2 (SEQ ID NO:708); miR-1270-1 (SEQ ID NO:707); miR-1271 (SEQ ID NO:709); miR-1272 (SEQ ID NO:710); miR-1273a (SEQ ID NO:711); miR-1273c (SEQ ID NO:712); miR-1273d (SEQ ID NO:713); miR-1273e (SEQ ID NO:714); miR-1273f (SEQ ID NO:715); miR-1273g (SEQ ID NO:716); miR-1273h (SEQ ID NO:717); miR-1275 (SEQ ID NO:718); miR-1276 (SEQ ID NO:719); miR-1277 (SEQ ID NO:720); miR-1278 (SEQ ID NO:721); miR-1279 (SEQ ID NO:722); miR-1281 (SEQ ID NO:723); miR-1282 (SEQ ID NO:724); miR-1283-2 (SEQ ID NO:726); miR-1283-1 (SEQ ID NO:725); miR-1284 (SEQ ID NO:727); miR-1285-2 (SEQ ID NO:729); miR-1285-1 (SEQ ID NO:728); miR-1286 (SEQ ID NO:730); miR-1287 (SEQ ID NO:731); miR-1288 (SEQ ID NO:732); miR-1289-2 (SEQ ID NO:734); miR-1289-1 (SEQ ID NO:733); miR-1290 (SEQ ID NO:735); miR-1291 (SEQ ID NO:736); miR-1292 (SEQ ID NO:737); miR-1293 (SEQ ID NO:738); miR-1294 (SEQ ID NO:739); miR-1295a (SEQ ID NO:740); miR-1295b (SEQ ID NO:741); miR-1296 (SEQ ID NO:742); miR-1297 (SEQ ID NO:743); miR-1298 (SEQ ID NO:744); miR-1299 (SEQ ID NO:745); miR-1301 (SEQ ID NO:746); miR-1302-11 (SEQ ID NO:749); miR-1302-10 (SEQ ID NO:748); miR-1302-9 (SEQ ID NO:757); miR-1302-8 (SEQ ID NO:756); miR-1302-7 (SEQ ID NO:755); miR-1302-6 (SEQ ID NO:754); miR-1302-5 (SEQ ID NO:753); miR-1302-4 (SEQ ID NO:752); miR-1302-3 (SEQ ID NO:751); miR-1302-2 (SEQ ID NO:750); miR-1302-1 (SEQ ID NO:747); miR-1303 (SEQ ID NO:758); miR-1304 (SEQ ID NO:759); miR-1305 (SEQ ID NO:760); miR-1306 (SEQ ID NO:761); miR-1307 (SEQ ID NO:762); miR-1321 (SEQ ID NO:763); miR-1322 (SEQ ID NO:764); miR-1323 (SEQ ID NO:765); miR-1324 (SEQ ID NO:766); miR-1343 (SEQ ID NO:767); miR-1468 (SEQ ID NO:768); miR-1469 (SEQ ID NO:769); miR-1470 (SEQ ID NO:770); miR-1471 (SEQ ID NO:771); miR-1537 (SEQ ID NO:772); miR-1538 (SEQ ID NO:773); miR-1539 (SEQ ID NO:774); miR-1587 (SEQ ID NO:775); miR-1825 (SEQ ID NO:776); miR-1827 (SEQ ID NO:777); miR-1908 (SEQ ID NO:778); miR-1909 (SEQ ID NO:779); miR-1910 (SEQ ID NO:780); miR-1911 (SEQ ID NO:781); miR-1912 (SEQ ID NO:782); miR-1913 (SEQ ID NO:783); miR-1914 (SEQ ID NO:784); miR-1915 (SEQ ID NO:785); miR-1972-2 (SEQ ID NO:787); miR-1972-1 (SEQ ID NO:786); miR-1973 (SEQ ID NO:788); miR-1976 (SEQ ID NO:789); miR-2052 (SEQ ID NO:790); miR-2053 (SEQ ID NO:791); miR-2054 (SEQ ID NO:792); miR-2110 (SEQ ID NO:793); miR-2113 (SEQ ID NO:794); miR-2114 (SEQ ID NO:795); miR-2115 (SEQ ID NO:796); miR-2116 (SEQ ID NO:797); miR-2117 (SEQ ID NO:798); miR-2276 (SEQ ID NO:799); miR-2277 (SEQ ID NO:800); miR-2278 (SEQ ID NO:801); miR-2355 (SEQ ID NO:802); miR-2392 (SEQ ID NO:803); miR-2467 (SEQ ID NO:804); miR-2681 (SEQ ID NO:805); miR-2682 (SEQ ID NO:806); miR-2861 (SEQ ID NO:807); miR-2909 (SEQ ID NO:808); miR-3064 (SEQ ID NO:809); miR-3065 (SEQ ID NO:810); miR-3074 (SEQ ID NO:811); miR-3115 (SEQ ID NO:812); miR-3116-2 (SEQ ID NO:814); miR-3116-1 (SEQ ID NO:813); miR-3117 (SEQ ID NO:815); miR-3118-6 (SEQ ID NO:821); miR-3118-5 (SEQ ID NO:820); miR-3118-4 (SEQ ID NO:819); miR-3118-3 (SEQ ID NO:818); miR-3118-2 (SEQ ID NO:817); miR-3118-1 (SEQ ID NO:816); miR-3119-2 (SEQ ID NO:823); miR-3119-1 (SEQ ID NO:822); miR-3120 (SEQ ID NO:824); miR-3121 (SEQ ID 22 (SEQ ID NO:826); miR-3123 (SEQ ID NO:827); miR-3124 (SEQ ID NO:828); miR-3125 (SEQ ID NO:829); miR-3126 (SEQ ID NO:830); miR-3127 (SEQ ID NO:831); miR-3128 (SEQ ID NO:832); miR-3129 (SEQ ID NO:833); miR-3130-2 (SEQ ID NO:835); miR-3130-1 (SEQ ID NO:834); miR-3131 (SEQ ID NO:836); miR-3132 (SEQ ID NO:837); miR-3133 (SEQ ID NO:838); miR-3134 (SEQ ID NO:839); miR-3135a (SEQ ID NO:840); miR-3135b (SEQ ID NO:841); miR-3136 (SEQ ID NO:842); miR-3137 (SEQ ID NO:843); miR-3138 (SEQ ID NO:844); miR-3139 (SEQ ID NO:845); miR-3140 (SEQ ID NO:846); miR-3141 (SEQ ID NO:847); miR-3142 (SEQ ID NO:848); miR-3143 (SEQ ID NO:849); miR-3144 (SEQ ID NO:850); miR-3145 (SEQ ID NO:851); miR-3146 (SEQ ID NO:852); miR-3147 (SEQ ID NO:853); miR-3148 (SEQ ID NO:854); miR-3149 (SEQ ID NO:855); miR-3150a (SEQ ID NO:856); miR-3150b (SEQ ID NO:857); miR-3151 (SEQ ID NO:858); miR-3152 (SEQ ID NO:859); miR-3153 (SEQ ID NO:860); miR-3154 (SEQ ID NO:861); miR-3155a (SEQ ID NO:862); miR-3155b (SEQ ID NO:863); miR-3156-3 (SEQ ID NO:866); miR-3156-2 (SEQ ID NO:865); miR-3156-1 (SEQ ID NO:864); miR-3157 (SEQ ID NO:867); miR-3158-2 (SEQ ID NO:869); miR-3158-1 (SEQ ID NO:868); miR-3159 (SEQ ID NO:870); miR-3160-2 (SEQ ID NO:872); miR-3160-1 (SEQ ID NO:871); miR-3161 (SEQ ID NO:873); miR-3162 (SEQ ID NO:874); miR-3163 (SEQ ID NO:875); miR-3164 (SEQ ID NO:876); miR-3165 (SEQ ID NO:877); miR-3166 (SEQ ID NO:878); miR-3167 (SEQ ID NO:879); miR-3168 (SEQ ID NO:880); miR-3169 (SEQ ID NO:881); miR-3170 (SEQ ID NO:882); miR-3171 (SEQ ID NO:883); miR-3173 (SEQ ID NO:884); miR-3174 (SEQ ID NO:885); miR-3175 (SEQ ID NO:886); miR-3176 (SEQ ID NO:887); miR-3177 (SEQ ID NO:888); miR-3178 (SEQ ID NO:889); miR-3179-3 (SEQ ID NO:892); miR-3179-2 (SEQ ID NO:891); miR-3179-1 (SEQ ID NO:890); miR-3180-5 (SEQ ID NO:897); miR-3180-4 (SEQ ID NO:896); miR-3180-3 (SEQ ID NO:895); miR-3180-2 (SEQ ID NO:894); miR-3180-1 (SEQ ID NO:893); miR-3181 (SEQ ID NO:898); miR-3182 (SEQ ID NO:899); miR-3183 (SEQ ID NO:900); miR-3184 (SEQ ID NO:901); miR-3185 (SEQ ID NO:902); miR-3186 (SEQ ID NO:903); miR-3187 (SEQ ID NO:904); miR-3188 (SEQ ID NO:905); miR-3189 (SEQ ID NO:906); miR-3190 (SEQ ID NO:907); miR-3191 (SEQ ID NO:908); miR-3192 (SEQ ID NO:909); miR-3193 (SEQ ID NO:910); miR-3194 (SEQ ID NO:911); miR-3195 (SEQ ID NO:912); miR-3196 (SEQ ID NO:913); miR-3197 (SEQ ID NO:914); miR-3198-2 (SEQ ID NO:916); miR-3198-1 (SEQ ID NO:915); miR-3199-2 (SEQ ID NO:918); miR-3199-1 (SEQ ID NO:917); miR-3200 (SEQ ID NO:919); miR-3201 (SEQ ID NO:920); miR-3202-2 (SEQ ID NO:922); miR-3202-1 (SEQ ID NO:921); miR-3529 (SEQ ID NO:923); miR-3591 (SEQ ID NO:924); miR-3605 (SEQ ID NO:925); miR-3606 (SEQ ID NO:926); miR-3607 (SEQ ID NO:927); miR-3609 (SEQ ID NO:928); miR-3610 (SEQ ID NO:929); miR-3611 (SEQ ID NO:930); miR-3612 (SEQ ID NO:931); miR-3613 (SEQ ID NO:932); miR-3614 (SEQ ID NO:933); miR-3615 (SEQ ID NO:934); miR-3616 (SEQ ID NO:935); miR-3617 (SEQ ID NO:936); miR-3618 (SEQ ID NO:937); miR-3619 (SEQ ID NO:938); miR-3620 (SEQ ID NO:939); miR-3621 (SEQ ID NO:940); miR-3622a (SEQ ID NO:941); miR-3622b (SEQ ID NO:942); miR-3646 (SEQ ID NO:943); miR-3648 (SEQ ID NO:944); miR-3649 (SEQ ID NO:945); miR-3650 (SEQ ID NO:946); miR-3651 (SEQ ID NO:947); miR-3652 (SEQ ID NO:948); miR-3653 (SEQ ID NO:949); miR-3654 (SEQ ID NO:950); miR-3655 (SEQ ID NO:951); miR-3656 (SEQ ID NO:952); miR-3657 (SEQ ID NO:953); miR-3658 (SEQ ID NO:954); miR-3659 (SEQ ID NO:955); miR-3660 (SEQ ID NO:956); miR-3661 (SEQ ID NO:957); miR-3662 (SEQ ID NO:958); miR-3663 (SEQ ID NO:959); miR-3664 (SEQ ID NO:960); miR-3665 (SEQ ID NO:961); miR-3666 (SEQ ID NO:962); miR-3667 (SEQ ID NO:963); miR-3668 (SEQ ID NO:964); miR-3669 (SEQ ID NO:965); miR-3670-2 (SEQ ID NO:967); miR-3670-1 (SEQ ID NO:966); miR-3671 (SEQ ID NO:968); miR-3672 (SEQ ID NO:969); miR-3673 (SEQ ID NO:970); miR-3674 (SEQ ID NO:971); miR-3675 (SEQ ID NO:972); miR-3677 (SEQ ID NO:973); miR-3678 (SEQ ID NO:974); miR-3679 (SEQ ID NO:975); miR-3680-2 (SEQ ID NO:977); miR-3680-1 (SEQ ID NO:976); miR-3681 (SEQ ID NO:978); miR-3682 (SEQ ID NO:979); miR-3683 (SEQ ID NO:980); miR-3684 (SEQ ID NO:981); miR-3685 (SEQ ID NO:982); miR-3686 (SEQ ID NO:983); miR-3687 (SEQ ID NO:984); miR-3688-2 (SEQ ID NO:986); miR-3688-1 (SEQ ID NO:985); miR-3689a (SEQ ID NO:987); miR-3689b (SEQ ID NO:988); miR-3689c (SEQ ID NO:989); miR-3689d-1 (SEQ ID NO:990); miR-3689d-2 (SEQ ID NO:991); miR-3689e (SEQ ID NO:992); miR-3689f (SEQ ID NO:993); miR-3690-2 (SEQ ID NO:995); miR-3690-1 (SEQ ID NO:994); miR-3691 (SEQ ID NO:996); miR-3692 (SEQ ID NO:997); miR-3713 (SEQ ID NO:998); miR-3714 (SEQ ID NO:999); miR-3907 (SEQ ID NO:1000); miR-3908 (SEQ ID NO:1001); miR-3909 (SEQ ID NO:1002); miR-3910-2 (SEQ ID NO:1004); miR-3910-1 (SEQ ID NO:1003); miR-3911 (SEQ ID NO:1005); miR-3912 (SEQ ID NO:1006); miR-3913-2 (SEQ ID NO:1008); miR-3913-1 (SEQ ID NO:1007); miR-3914-2 (SEQ ID NO:1010); miR-3914-1 (SEQ ID NO:1009); miR-3915 (SEQ ID NO:1011); miR-3916 (SEQ ID NO:1012); miR-3917 (SEQ ID NO:1013); miR-3918 (SEQ ID NO:1014); miR-3919 (SEQ ID NO:1015); miR-3920 (SEQ ID NO:1016); miR-3921 (SEQ ID NO:1017); miR-3922 (SEQ ID NO:1018); miR-3923 (SEQ ID NO:1019); miR-3924 (SEQ ID NO:1020); miR-3925 (SEQ ID NO:1021); miR-3926-2 (SEQ ID NO:1023); miR-3926-1 (SEQ ID NO:1022); miR-3927 (SEQ ID NO:1024); miR-3928 (SEQ ID NO:1025); miR-3929 (SEQ ID NO:1026); miR-3934 (SEQ ID NO:1027); miR-3935 (SEQ ID NO:1028); miR-3936 (SEQ ID NO:1029); miR-3937 (SEQ ID NO:1030); miR-3938 (SEQ ID NO:1031); miR-3939 (SEQ ID NO:1032); miR-3940 (SEQ ID NO:1033); miR-3941 (SEQ ID NO:1034); miR-3942 (SEQ ID NO:1035); miR-3943 (SEQ ID NO:1036); miR-3944 (SEQ ID NO:1037); miR-3945 (SEQ ID NO:1038); miR-3960 (SEQ ID NO:1039); miR-3972 (SEQ ID NO:1040); miR-3973 (SEQ ID NO:1041); miR-3974 (SEQ ID NO:1042); miR-3975 (SEQ ID NO:1043); miR-3976 (SEQ ID NO:1044); miR-3977 (SEQ ID NO:1045); miR-3978 (SEQ ID NO:1046); miR-4251 (SEQ ID NO:1047); miR-4252 (SEQ ID NO:1048); miR-4253 (SEQ ID NO:1049); miR-4254 (SEQ ID NO:1050); miR-4255 (SEQ ID NO:1051); miR-4256 (SEQ ID NO:1052); miR-4257 (SEQ ID NO:1053); miR-4258 (SEQ ID NO:1054); miR-4259 (SEQ ID NO:1055); miR-4260 (SEQ ID NO:1056); miR-4261 (SEQ ID NO:1057); miR-4262 (SEQ ID NO:1058); miR-4263 (SEQ ID NO:1059); miR-4264 (SEQ ID NO:1060); miR-4265 (SEQ ID NO:1061); miR-4266 (SEQ ID NO:1062); miR-4267 (SEQ ID NO:1063); miR-4268 (SEQ ID NO:1064); miR-4269 (SEQ ID NO:1065); miR-4270 (SEQ ID NO:1066); miR-4271 (SEQ ID NO:1067); miR-4272 (SEQ ID NO:1068); miR-4273 (SEQ ID NO:1069); miR-4274 (SEQ ID NO:1070); miR-4275 (SEQ ID NO:1071); miR-4276 (SEQ ID NO:1072); miR-4277 (SEQ ID NO:1073); miR-4278 (SEQ ID NO:1074); miR-4279 (SEQ ID NO:1075); miR-4280 (SEQ ID NO:1076); miR-4281 (SEQ ID NO:1077); miR-4282 (SEQ ID NO:1078); miR-4283-2 (SEQ ID NO:1080); miR-4283-1 (SEQ ID NO:1079); miR-4284 (SEQ ID NO:1081); miR-4285 (SEQ ID NO:1082); miR-4286 (SEQ ID NO:1083); miR-4287 (SEQ ID NO:1084); miR-4288 (SEQ ID NO:1085); miR-4289 (SEQ ID NO:1086); miR-4290 (SEQ ID NO:1087); miR-4291 (SEQ ID NO:1088); miR-4292 (SEQ ID NO:1089); miR-4293 (SEQ ID NO:1090); miR-4294 (SEQ ID NO:1091); miR-4295 (SEQ ID NO:1092); miR-4296 (SEQ ID NO:1093); miR-4297 (SEQ ID NO:1094); miR-4298 (SEQ ID NO:1095); miR-4299 (SEQ ID NO:1096); miR-4300 (SEQ ID NO:1097); miR-4301 (SEQ ID NO:1098); miR-4302 (SEQ ID NO:1099); miR-4303 (SEQ ID NO:1100); miR-4304 (SEQ ID NO:1101); miR-4305 (SEQ ID NO:1102); miR-4306 (SEQ ID NO:1103); miR-4307 (SEQ ID NO:1104); miR-4308 (SEQ ID NO:1105); miR-4309 (SEQ ID NO:1106); miR-4310 (SEQ ID NO:1107); miR-4311 (SEQ ID NO:1108); miR-4312 (SEQ ID NO:1109); miR-4313 (SEQ ID NO:1110); miR-4314 (SEQ ID NO:1111); miR-4315-2 (SEQ ID NO:1113); miR-4315-1 (SEQ ID NO:1112); miR-4316 (SEQ ID NO:1114); miR-4317 (SEQ ID NO:1115); miR-4318 (SEQ ID NO:1116); miR-4319 (SEQ ID NO:1117); miR-4320 (SEQ ID NO:1118); miR-4321 (SEQ ID NO:1119); miR-4322 (SEQ ID NO:1120); miR-4323 (SEQ ID NO:1121); miR-4324 (SEQ ID NO:1122); miR-4325 (SEQ ID NO:1123); miR-4326 (SEQ ID NO:1124); miR-4327 (SEQ ID NO:1125); miR-4328 (SEQ ID NO:1126); miR-4329 (SEQ ID NO:1127); miR-4330 (SEQ ID NO:1128); miR-4417 (SEQ ID NO:1129); miR-4418 (SEQ ID NO:1130); miR-4419a (SEQ ID NO:1131); miR-4419b (SEQ ID NO:1132); miR-4420 (SEQ ID NO:1133); miR-4421 (SEQ ID NO:1134); miR-4422 (SEQ ID NO:1135); miR-4423 (SEQ ID NO:1136); miR-4424 (SEQ ID NO:1137); miR-4425 (SEQ ID NO:1138); miR-4426 (SEQ ID NO:1139); miR-4427 (SEQ ID NO:1140); miR-4428 (SEQ ID NO:1141); miR-4429 (SEQ ID NO:1142); miR-4430 (SEQ ID NO:1143); miR-4431 (SEQ ID NO:1144); miR-4432 (SEQ ID NO:1145); miR-4433b (SEQ ID NO:1147); miR-4433 (SEQ ID NO:1146); miR-4434 (SEQ ID NO:1148); miR-4435-2 (SEQ ID NO:1150); miR-4435-1 (SEQ ID NO:1149); miR-4436a (SEQ ID NO:1151); miR-4436b-1 (SEQ ID NO:1152); miR-4436b-2 (SEQ ID NO:1153); miR-4437 (SEQ ID NO:1154); miR-4438 (SEQ ID NO:1155); miR-4439 (SEQ ID NO:1156); miR-4440 (SEQ ID NO:1157); miR-4441 (SEQ ID NO:1158); miR-4442 (SEQ ID NO:1159); miR-4443 (SEQ ID NO:1160); miR-4444-2 (SEQ ID NO:1162); miR-4444-1 (SEQ ID NO:1161); miR-4445 (SEQ ID NO:1163); miR-4446 (SEQ ID NO:1164); miR-4447 (SEQ ID NO:1165); miR-4448 (SEQ ID NO:1166); miR-4449 (SEQ ID NO:1167); miR-4450 (SEQ ID NO:1168); miR-4451 (SEQ ID NO:1169); miR-4452 (SEQ ID NO:1170); miR-4453 (SEQ ID NO:1171); miR-4454 (SEQ ID NO:1172); miR-4455 (SEQ ID NO:1173); miR-4456 (SEQ ID NO:1174); miR-4457 (SEQ ID NO:1175); miR-4458 (SEQ ID NO:1176); miR-4459 (SEQ ID NO:1177); miR-4460 (SEQ ID NO:1178); miR-4461 (SEQ ID NO:1179); miR-4462 (SEQ ID NO:1180); miR-4463 (SEQ ID NO:1181); miR-4464 (SEQ ID NO:1182); miR-4465 (SEQ ID NO:1183); miR-4466 (SEQ ID NO:1184); miR-4467 (SEQ ID NO:1185); miR-4468 (SEQ ID NO:1186); miR-4469 (SEQ ID NO:1187); miR-4470 (SEQ ID NO:1188); miR-4471 (SEQ ID NO:1189); miR-4472-2 (SEQ ID NO:1191); miR-4472-1 (SEQ ID NO:1190); miR-4473 (SEQ ID NO:1192); miR-4474 (SEQ ID NO:1193); miR-4475 (SEQ ID NO:1194); miR-4476 (SEQ ID NO:1195); miR-4477a (SEQ ID NO:1196); miR-4477b (SEQ ID NO:1197); miR-4478 (SEQ ID NO:1198); miR-4479 (SEQ ID NO:1199); miR-4480 (SEQ ID NO:1200); miR-4481 (SEQ ID NO:1201); miR-4482 (SEQ ID NO:1202); miR-4483 (SEQ ID NO:1203); miR-4484 (SEQ ID NO:1204); miR-4485 (SEQ ID NO:1205); miR-4486 (SEQ ID NO:1206); miR-4487 (SEQ ID NO:1207); miR-4488 (SEQ ID NO:1208); miR-4489 (SEQ ID NO:1209); miR-4490 (SEQ ID NO:1210); miR-4491 (SEQ ID NO:1211); miR-4492 (SEQ ID NO:1212); miR-4493 (SEQ ID NO:1213); miR-4494 (SEQ ID NO:1214); miR-4495 (SEQ ID NO:1215); miR-4496 (SEQ ID NO:1216); miR-4497 (SEQ ID NO:1217); miR-4498 (SEQ ID NO:1218); miR-4499 (SEQ ID NO:1219); miR-4500 (SEQ ID NO:1220); miR-4501 (SEQ ID NO:1221); miR-4502 (SEQ ID NO:1222); miR-4503 (SEQ ID NO:1223); miR-4504 (SEQ ID NO:1224); miR-4505 (SEQ ID NO:1225); miR-4506 (SEQ ID NO:1226); miR-4507 (SEQ ID NO:1227); miR-4508 (SEQ ID NO:1228); miR-4509-3 (SEQ ID NO:1231); miR-4509-2 (SEQ ID NO:1230); miR-4509-1 (SEQ ID NO:1229); miR-4510 (SEQ ID NO:1232); miR-4511 (SEQ ID NO:1233); miR-4512 (SEQ ID NO:1234); miR-4513 (SEQ ID NO:1235); miR-4514 (SEQ ID NO:1236); miR-4515 (SEQ ID NO:1237); miR-4516 (SEQ ID NO:1238); miR-4517 (SEQ ID NO:1239); miR-4518 (SEQ ID NO:1240); miR-4519 (SEQ ID NO:1241); miR-4520a (SEQ ID NO:1242); miR-4520b (SEQ ID NO:1243); miR-4521 (SEQ ID NO:1244); miR-4522 (SEQ ID NO:1245); miR-4523 (SEQ ID NO:1246); miR-4524a (SEQ ID NO:1247); miR-4524b (SEQ ID NO:1248); miR-4525 (SEQ ID NO:1249); miR-4526 (SEQ ID NO:1250); miR-4527 (SEQ ID NO:1251); miR-4528 (SEQ ID NO:1252); miR-4529 (SEQ ID NO:1253); miR-4530 (SEQ ID NO:1254); miR-4531 (SEQ ID NO:1255); miR-4532 (SEQ ID NO:1256); miR-4533 (SEQ ID NO:1257); miR-4534 (SEQ ID NO:1258); miR-4535 (SEQ ID NO:1259); miR-4536-2 (SEQ ID NO:1261); miR-4536-1 (SEQ ID NO:1260); miR-4537 (SEQ ID NO:1262); miR-4538 (SEQ ID NO:1263); miR-4539 (SEQ ID NO:1264); miR-4540 (SEQ ID NO:1265); miR-4632 (SEQ ID NO:1266); miR-4633 (SEQ ID NO:1267); miR-4634 (SEQ ID NO:1268); miR-4635 (SEQ ID NO:1269); miR-4636 (SEQ ID NO:1270); miR-4637 (SEQ ID NO:1271); miR-4638 (SEQ ID NO:1272); miR-4639 (SEQ ID NO:1273); miR-4640 (SEQ ID NO:1274); miR-4641 (SEQ ID NO:1275); miR-4642 (SEQ ID NO:1276); miR-4643 (SEQ ID NO:1277); miR-4644 (SEQ ID NO:1278); miR-4645 (SEQ ID NO:1279); miR-4646 (SEQ ID NO:1280); miR-4647 (SEQ ID NO:1281); miR-4648 (SEQ ID NO:1282); miR-4649 (SEQ ID NO:1283); miR-4650-2 (SEQ ID NO:1285); miR-4650-1 (SEQ ID NO:1284); miR-4651 (SEQ ID NO:1286); miR-4652 (SEQ ID NO:1287); miR-4653 (SEQ ID NO:1288); miR-4654 (SEQ ID NO:1289); miR-4655 (SEQ ID NO:1290); miR-4656 (SEQ ID NO:1291); miR-4657 (SEQ ID NO:1292); miR-4658 (SEQ ID NO:1293); miR-4659a (SEQ ID NO:1294); miR-4659b (SEQ ID NO:1295); miR-4660 (SEQ ID NO:1296); miR-4661 (SEQ ID NO:1297); miR-4662a (SEQ ID NO:1298); miR-4662b (SEQ ID NO:1299); miR-4663 (SEQ ID NO:1300); miR-4664 (SEQ ID NO:1301); miR-4665 (SEQ ID NO:1302); miR-4666a (SEQ ID NO:1303); miR-4666b (SEQ ID NO:1304); miR-4667 (SEQ ID NO:1305); miR-4668 (SEQ ID NO:1306); miR-4669 (SEQ ID NO:1307); miR-4670 (SEQ ID NO:1308); miR-4671 (SEQ ID NO:1309); miR-4672 (SEQ ID NO:1310); miR-4673 (SEQ ID NO:1311); miR-4674 (SEQ ID NO:1312); miR-4675 (SEQ ID NO:1313); miR-4676 (SEQ ID NO:1314); miR-4677 (SEQ ID NO:1315); miR-4678 (SEQ ID NO:1316); miR-4679-2 (SEQ ID NO:1318); miR-4679-1 (SEQ ID NO:1317); miR-4680 (SEQ ID NO:1319); miR-4681 (SEQ ID NO:1320); miR-4682 (SEQ ID NO:1321); miR-4683 (SEQ ID NO:1322); miR-4684 (SEQ ID NO:1323); miR-4685 (SEQ ID NO:1324); miR-4686 (SEQ ID NO:1325); miR-4687 (SEQ ID NO:1326); miR-4688 (SEQ ID NO:1327); miR-4689 (SEQ ID NO:1328); miR-4690 (SEQ ID NO:1329); miR-4691 (SEQ ID NO:1330); miR-4692 (SEQ ID NO:1331); miR-4693 (SEQ ID NO:1332); miR-4694 (SEQ ID NO:1333); miR-4695 (SEQ ID NO:1334); miR-4696 (SEQ ID NO:1335); miR-4697 (SEQ ID NO:1336); miR-4698 (SEQ ID NO:1337); miR-4699 (SEQ ID NO:1338); miR-4700 (SEQ ID NO:1339); miR-4701 (SEQ ID NO:1340); miR-4703 (SEQ ID NO:1341); miR-4704 (SEQ ID NO:1342); miR-4705 (SEQ ID NO:1343); miR-4706 (SEQ ID NO:1344); miR-4707 (SEQ ID NO:1345); miR-4708 (SEQ ID NO:1346); miR-4709 (SEQ ID NO:1347); miR-4710 (SEQ ID NO:1348); miR-4711 (SEQ ID NO:1349); miR-4712 (SEQ ID NO:1350); miR-4713 (SEQ ID NO:1351); miR-4714 (SEQ ID NO:1352); miR-4715 (SEQ ID NO:1353); miR-4716 (SEQ ID NO:1354); miR-4717 (SEQ ID NO:1355); miR-4718 (SEQ ID NO:1356); miR-4719 (SEQ ID NO:1357); miR-4720 (SEQ ID NO:1358); miR-4721 (SEQ ID NO:1359); miR-4722 (SEQ ID NO:1360); miR-4723 (SEQ ID NO:1361); miR-4724 (SEQ ID NO:1362); miR-4725 (SEQ ID NO:1363); miR-4726 (SEQ ID NO:1364); miR-4727 (SEQ ID NO:1365); miR-4728 (SEQ ID NO:1366); miR-4729 (SEQ ID NO:1367); miR-4730 (SEQ ID NO:1368); miR-4731 (SEQ ID NO:1369); miR-4732 (SEQ ID NO:1370); miR-4733 (SEQ ID NO:1371); miR-4734 (SEQ ID NO:1372); miR-4735 (SEQ ID NO:1373); miR-4736 (SEQ ID NO:1374); miR-4737 (SEQ ID NO:1375); miR-4738 (SEQ ID NO:1376); miR-4739 (SEQ ID NO:1377); miR-4740 (SEQ ID NO:1378); miR-4741 (SEQ ID NO:1379); miR-4742 (SEQ ID NO:1380); miR-4743 (SEQ ID NO:1381); miR-4744 (SEQ ID NO:1382); miR-4745 (SEQ ID NO:1383); miR-4746 (SEQ ID NO:1384); miR-4747 (SEQ ID NO:1385); miR-4748 (SEQ ID NO:1386); miR-4749 (SEQ ID NO:1387); miR-4750 (SEQ ID NO:1388); miR-4751 (SEQ ID NO:1389); miR-4752 (SEQ ID NO:1390); miR-4753 (SEQ ID NO:1391); miR-4754 (SEQ ID NO:1392); miR-4755 (SEQ ID NO:1393); miR-4756 (SEQ ID NO:1394); miR-4757 (SEQ ID NO:1395); miR-4758 (SEQ ID NO:1396); miR-4759 (SEQ ID NO:1397); miR-4760 (SEQ ID NO:1398); miR-4761 (SEQ ID NO:1399); miR-4762 (SEQ ID NO:1400); miR-4763 (SEQ ID NO:1401); miR-4764 (SEQ ID NO:1402); miR-4765 (SEQ ID NO:1403); miR-4766 (SEQ ID NO:1404); miR-4767 (SEQ ID NO:1405); miR-4768 (SEQ ID NO:1406); miR-4769 (SEQ ID NO:1407); miR-4770 (SEQ ID NO:1408); miR-4771-2 (SEQ ID NO:1410); miR-4771-1 (SEQ ID NO:1409); miR-4772 (SEQ ID NO:1411); miR-4773-2 (SEQ ID NO:1413); miR-4773-1 (SEQ ID NO:1412); miR-4774 (SEQ ID NO:1414); miR-4775 (SEQ ID NO:1415); miR-4776-2 (SEQ ID NO:1417); miR-4776-1 (SEQ ID NO:1416); miR-4777 (SEQ ID NO:1418); miR-4778 (SEQ ID NO:1419); miR-4779 (SEQ ID NO:1420); miR-4780 (SEQ ID NO:1421); miR-4781 (SEQ ID NO:1422); miR-4782 (SEQ ID NO:1423); miR-4783 (SEQ ID NO:1424); miR-4784 (SEQ ID NO:1425); miR-4785 (SEQ ID NO:1426); miR-4786 (SEQ ID NO:1427); miR-4787 (SEQ ID NO:1428); miR-4788 (SEQ ID NO:1429); miR-4789 (SEQ ID NO:1430); miR-4790 (SEQ ID NO:1431); miR-4791 (SEQ ID NO:1432); miR-4792 (SEQ ID NO:1433); miR-4793 (SEQ ID NO:1434); miR-4794 (SEQ ID NO:1435); miR-4795 (SEQ ID NO:1436); miR-4796 (SEQ ID NO:1437); miR-4797 (SEQ ID NO:1438); miR-4798 (SEQ ID NO:1439); miR-4799 (SEQ ID NO:1440); miR-4800 (SEQ ID NO:1441); miR-4801 (SEQ ID NO:1442); miR-4802 (SEQ ID NO:1443); miR-4803 (SEQ ID NO:1444); miR-4804 (SEQ ID NO:1445); miR-4999 (SEQ ID NO:1446); miR-5000 (SEQ ID NO:1447); miR-5001 (SEQ ID NO:1448); miR-5002 (SEQ ID NO:1449); miR-5003 (SEQ ID NO:1450); miR-5004 (SEQ ID NO:1451); miR-5006 (SEQ ID NO:1452); miR-5007 (SEQ ID NO:1453); miR-5008 (SEQ ID NO:1454); miR-5009 (SEQ ID NO:1455); miR-5010 (SEQ ID NO:1456); miR-5011 (SEQ ID NO:1457); miR-5047 (SEQ ID NO:1458); miR-5087 (SEQ ID NO:1459); miR-5088 (SEQ ID NO:1460); miR-5089 (SEQ ID NO:1461); miR-5090 (SEQ ID NO:1462); miR-5091 (SEQ ID NO:1463); miR-5092 (SEQ ID NO:1464); miR-5093 (SEQ ID NO:1465); miR-5094 (SEQ ID NO:1466); miR-5095 (SEQ ID NO:1467); miR-5096 (SEQ ID NO:1468); miR-5100 (SEQ ID NO:1469); miR-5186 (SEQ ID NO:1470); miR-5187 (SEQ ID NO:1471); miR-5188 (SEQ ID NO:1472); miR-5189 (SEQ ID NO:1473); miR-5190 (SEQ ID NO:1474); miR-5191 (SEQ ID NO:1475); miR-5192 (SEQ ID NO:1476); miR-5193 (SEQ ID NO:1477); miR-5194 (SEQ ID NO:1478); miR-5195 (SEQ ID NO:1479); miR-5196 (SEQ ID NO:1480); miR-5197 (SEQ ID NO:1481); miR-5571 (SEQ ID NO:1482); miR-5572 (SEQ ID NO:1483); miR-5579 (SEQ ID NO:1484); miR-5580 (SEQ ID NO:1485); miR-5581 (SEQ ID NO:1486); miR-5582 (SEQ ID NO:1487); miR-5583-2 (SEQ ID NO:1489); miR-5583-1 (SEQ ID NO:1488); miR-5584 (SEQ ID NO:1490); miR-5585 (SEQ ID NO:1491); miR-5586 (SEQ ID NO:1492); miR-5587 (SEQ ID NO:1493); miR-5588 (SEQ ID NO:1494); miR-5589 (SEQ ID NO:1495); miR-5590 (SEQ ID NO:1496); miR-5591 (SEQ ID NO:1497); miR-5680 (SEQ ID NO:1498); miR-5681a (SEQ ID NO:1499); miR-5681b (SEQ ID NO:1500); miR-5682 (SEQ ID NO:1501); miR-5683 (SEQ ID NO:1502); miR-5684 (SEQ ID NO:1503); miR-5685 (SEQ ID NO:1504); miR-5687 (SEQ ID NO:1505); miR-5688 (SEQ ID NO:1506); miR-5689 (SEQ ID NO:1507); miR-5690 (SEQ ID NO:1508); miR-5691 (SEQ ID NO:1509); miR-5692a-1 (SEQ ID NO:1510); miR-5692a-2 (SEQ ID NO:1511); miR-5692b (SEQ ID NO:1512); miR-5692c-1 (SEQ ID NO:1513); miR-5692c-2 (SEQ ID NO:1514); miR-5693 (SEQ ID NO:1515); miR-5694 (SEQ ID NO:1516); miR-5695 (SEQ ID NO:1517); miR-5696 (SEQ ID NO:1518); miR-5697 (SEQ ID NO:1519); miR-5698 (SEQ ID NO:1520); miR-5699 (SEQ ID NO:1521); miR-5700 (SEQ ID NO:1522); miR-5701-2 (SEQ ID NO:1524); miR-5701-1 (SEQ ID NO:1523); miR-5702 (SEQ ID NO:1525); miR-5703 (SEQ ID NO:1526); miR-5704 (SEQ ID NO:1527); miR-5705 (SEQ ID NO:1528); miR-5706 (SEQ ID NO:1529); miR-5707 (SEQ ID NO:1530); miR-5708 (SEQ ID NO:1531); miR-5739 (SEQ ID NO:1532); miR-5787 (SEQ ID NO:1533); miR-6068 (SEQ ID NO:1534); miR-6069 (SEQ ID NO:1535); miR-6070 (SEQ ID NO:1536); miR-6071 (SEQ ID NO:1537); miR-6072 (SEQ ID NO:1538); miR-6073 (SEQ ID NO:1539); miR-6074 (SEQ ID NO:1540); miR-6075 (SEQ ID NO:1541); miR-6076 (SEQ ID NO:1542); miR-6077-2 (SEQ ID NO:1544); miR-6077-1 (SEQ ID NO:1543); miR-6078 (SEQ ID NO:1545); miR-6079 (SEQ ID NO:1546); miR-6080 (SEQ ID NO:1547); miR-6081 (SEQ ID NO:1548); miR-6082 (SEQ ID NO:1549); miR-6083 (SEQ ID NO:1550); miR-6084 (SEQ ID NO:1551); miR-6085 (SEQ ID NO:1552); miR-6086 (SEQ ID NO:1553); miR-6087 (SEQ ID NO:1554); miR-6088 (SEQ ID NO:1555); miR-6089-2 (SEQ ID NO:1557); miR-6089-1 (SEQ ID NO:1556); miR-6090 (SEQ ID NO:1558); miR-6124 (SEQ ID NO:1559); miR-6125 (SEQ ID NO:1560); miR-6126 (SEQ ID NO:1561); miR-6127 (SEQ ID NO:1562); miR-6128 (SEQ ID NO:1563); miR-6129 (SEQ ID NO:1564); miR-6130 (SEQ ID NO:1565); miR-6131 (SEQ ID NO:1566); miR-6132 (SEQ ID NO:1567); miR-6133 (SEQ ID NO:1568); miR-6134 (SEQ ID NO:1569); miR-6165 (SEQ ID NO:1570); miR-6499 (SEQ ID NO:1571); miR-6500 (SEQ ID NO:1572); miR-6501 (SEQ ID NO:1573); miR-6502 (SEQ ID NO:1574); miR-6503 (SEQ ID NO:1575); miR-6504 (SEQ ID NO:1576); miR-6505 (SEQ ID NO:1577); miR-6506 (SEQ ID NO:1578); miR-6507 (SEQ ID NO:1579); miR-6508 (SEQ ID NO:1580); miR-6509 (SEQ ID NO:1581); miR-6510 (SEQ ID NO:1582); miR-6511a-1 (SEQ ID NO:1583); miR-6511a-2 (SEQ ID NO:1584); miR-6511a-3 (SEQ ID NO:1585); miR-6511a-4 (SEQ ID NO:1586); miR-6511b-1 (SEQ ID NO:1587); miR-6511b-2 (SEQ ID NO:1588); miR-6512 (SEQ ID NO:1589); miR-6513 (SEQ ID NO:1590); miR-6514 (SEQ ID NO:1591); miR-6515 (SEQ ID NO:1592); miR-6516 (SEQ ID NO:1593); miR-6715a (SEQ ID NO:1594); miR-6715b (SEQ ID NO:1595); miR-6716 (SEQ ID NO:1596); miR-6717 (SEQ ID NO:1597); miR-6718 (SEQ ID NO:1598); miR-6719 (SEQ ID NO:1599); miR-6720 (SEQ ID NO:1600); miR-6721 (SEQ ID NO:1601); miR-6722 (SEQ ID NO:1602); miR-6723 (SEQ ID NO:1603); miR-6724 (SEQ ID NO:1604); miR-6726 (SEQ ID NO:1605); miR-6727 (SEQ ID NO:1606); miR-6728 (SEQ ID NO:1607); miR-6729 (SEQ ID NO:1608); miR-6730 (SEQ ID NO:1609); miR-6731 (SEQ ID NO:1610); miR-6732 (SEQ ID NO:1611); miR-6733 (SEQ ID NO:1612); miR-6734 (SEQ ID NO:1613); miR-6735 (SEQ ID NO:1614); miR-6736 (SEQ ID NO:1615); miR-6737 (SEQ ID NO:1616); miR-6738 (SEQ ID NO:1617); miR-6739 (SEQ ID NO:1618); miR-6740 (SEQ ID NO:1619); miR-6741 (SEQ ID NO:1620); miR-6742 (SEQ ID NO:1621); miR-6743 (SEQ ID NO:1622); miR-6744 (SEQ ID NO:1623); miR-6745 (SEQ ID NO:1624); miR-6746 (SEQ ID NO:1625); miR-6747 (SEQ ID NO:1626); miR-6748 (SEQ ID NO:1627); miR-6749 (SEQ ID NO:1628); miR-6750 (SEQ ID NO:1629); miR-6751 (SEQ ID NO:1630); miR-6752 (SEQ ID NO:1631); miR-6753 (SEQ ID NO:1632); miR-6754 (SEQ ID NO:1633); miR-6755 (SEQ ID NO:1634); miR-6756 (SEQ ID NO:1635); miR-6757 (SEQ ID NO:1636); miR-6758 (SEQ ID NO:1637); miR-6759 (SEQ ID NO:1638); miR-6760 (SEQ ID NO:1639); miR-6761 (SEQ ID NO:1640); miR-6762 (SEQ ID NO:1641); miR-6763 (SEQ ID NO:1642); miR-6764 (SEQ ID NO:1643); miR-6765 (SEQ ID NO:1644); miR-6766 (SEQ ID NO:1645); miR-6767 (SEQ ID NO:1646); miR-6768 (SEQ ID NO:1647); miR-6769a (SEQ ID NO:1648); miR-6769b (SEQ ID NO:1649); miR-6770-3 (SEQ ID NO:1652); miR-6770-2 (SEQ ID NO:1651); miR-6770-1 (SEQ ID NO:1650); miR-6771 (SEQ ID NO:1653); miR-6772 (SEQ ID NO:1654); miR-6773 (SEQ ID NO:1655); miR-6774 (SEQ ID NO:1656); miR-6775 (SEQ ID NO:1657); miR-6776 (SEQ ID NO:1658); miR-6777 (SEQ ID NO:1659); miR-6778 (SEQ ID NO:1660); miR-6779 (SEQ ID NO:1661); miR-6780a (SEQ ID NO:1662); miR-6780b (SEQ ID NO:1663); miR-6781 (SEQ ID NO:1664); miR-6782 (SEQ ID NO:1665); miR-6783 (SEQ ID NO:1666); miR-6784 (SEQ ID NO:1667); miR-6785 (SEQ ID NO:1668); miR-6786 (SEQ ID NO:1669); miR-6787 (SEQ ID NO:1670); miR-6788 (SEQ ID NO:1671); miR-6789 (SEQ ID NO:1672); miR-6790 (SEQ ID NO:1673); miR-6791 (SEQ ID NO:1674); miR-6792 (SEQ ID NO:1675); miR-6793 (SEQ ID NO:1676); miR-6794 (SEQ ID NO:1677); miR-6795 (SEQ ID NO:1678); miR-6796 (SEQ ID NO:1679); miR-6797 (SEQ ID NO:1680); miR-6798 (SEQ ID NO:1681); miR-6799 (SEQ ID NO:1682); miR-6800 (SEQ ID NO:1683); miR-6801 (SEQ ID NO:1684); miR-6802 (SEQ ID NO:1685); miR-6803 (SEQ ID NO:1686); miR-6804 (SEQ ID NO:1687); miR-6805 (SEQ ID NO:1688); miR-6806 (SEQ ID NO:1689); miR-6807 (SEQ ID NO:1690); miR-6808 (SEQ ID NO:1691); miR-6809 (SEQ ID NO:1692); miR-6810 (SEQ ID NO:1693); miR-6811 (SEQ ID NO:1694); miR-6812 (SEQ ID NO:1695); miR-6813 (SEQ ID NO:1696); miR-6814 (SEQ ID NO:1697); miR-6815 (SEQ ID NO:1698); miR-6816 (SEQ ID NO:1699); miR-6817 (SEQ ID NO:1700); miR-6818 (SEQ ID NO:1701); miR-6819 (SEQ ID NO:1702); miR-6820 (SEQ ID NO:1703); miR-6821 (SEQ ID NO:1704); miR-6822 (SEQ ID NO:1705); miR-6823 (SEQ ID NO:1706); miR-6824 (SEQ ID NO:1707); miR-6825 (SEQ ID NO:1708); miR-6826 (SEQ ID NO:1709); miR-6827 (SEQ ID NO:1710); miR-6828 (SEQ ID NO:1711); miR-6829 (SEQ ID NO:1712); miR-6830 (SEQ ID NO:1713); miR-6831 (SEQ ID NO:1714); miR-6832 (SEQ ID NO:1715); miR-6833 (SEQ ID NO:1716); miR-6834 (SEQ ID NO:1717); miR-6835 (SEQ ID NO:1718); miR-6836 (SEQ ID NO:1719); miR-6837 (SEQ ID NO:1720); miR-6838 (SEQ ID NO:1721); miR-6839 (SEQ ID NO:1722); miR-6840 (SEQ ID NO:1723); miR-6841 (SEQ ID NO:1724); miR-6842 (SEQ ID NO:1725); miR-6843 (SEQ ID NO:1726); miR-6844 (SEQ ID NO:1727); miR-6845 (SEQ ID NO:1728); miR-6846 (SEQ ID NO:1729); miR-6847 (SEQ ID NO:1730); miR-6848 (SEQ ID NO:1731); miR-6849 (SEQ ID NO:1732); miR-6850 (SEQ ID NO:1733); miR-6851 (SEQ ID NO:1734); miR-6852 (SEQ ID NO:1735); miR-6853 (SEQ ID NO:1736); miR-6854 (SEQ ID NO:1737); miR-6855 (SEQ ID NO:1738); miR-6856 (SEQ ID NO:1739); miR-6857 (SEQ ID NO:1740); miR-6858 (SEQ ID NO:1741); miR-6859-3 (SEQ ID NO:1744); miR-6859-2 (SEQ ID NO:1743); miR-6859-1 (SEQ ID NO:1742); miR-6860 (SEQ ID NO:1745); miR-6861 (SEQ ID NO:1746); miR-6862-2 (SEQ ID NO:1748); miR-6862-1 (SEQ ID NO:1747); miR-6863 (SEQ ID NO:1749); miR-6864 (SEQ ID NO:1750); miR-6865 (SEQ ID NO:1751); miR-6866 (SEQ ID NO:1752); miR-6867 (SEQ ID NO:1753); miR-6868 (SEQ ID NO:1754); miR-6869 (SEQ ID NO:1755); miR-6870 (SEQ ID NO:1756); miR-6871 (SEQ ID NO:1757); miR-6872 (SEQ ID NO:1758); miR-6873 (SEQ ID NO:1759); miR-6874 (SEQ ID NO:1760); miR-6875 (SEQ ID NO:1761); miR-6876 (SEQ ID NO:1762); miR-6877 (SEQ ID NO:1763); miR-6878 (SEQ ID NO:1764); miR-6879 (SEQ ID NO:1765); miR-6880 (SEQ ID NO:1766); miR-6881 (SEQ ID NO:1767); miR-6882 (SEQ ID NO:1768); miR-6883 (SEQ ID NO:1769); miR-6884 (SEQ ID NO:1770); miR-6885 (SEQ ID NO:1771); miR-6886 (SEQ ID NO:1772); miR-6887 (SEQ ID NO:1773); miR-6888 (SEQ ID NO:1774); miR-6889 (SEQ ID NO:1775); miR-6890 (SEQ ID NO:1776); miR-6891 (SEQ ID NO:1777); miR-6892 (SEQ ID NO:1778); miR-6893 (SEQ ID NO:1779); miR-6894 (SEQ ID NO:1780); miR-6895 (SEQ ID NO:1781); miR-7106 (SEQ ID NO:1782); miR-7107 (SEQ ID NO:1783); miR-7108 (SEQ ID NO:1784); miR-7109 (SEQ ID NO:1785); miR-7110 (SEQ ID NO:1786); miR-7111 (SEQ ID NO:1787); miR-7112-2 (SEQ ID NO:1789); miR-7112-1 (SEQ ID NO:1788); miR-7113 (SEQ ID NO:1790); miR-7114 (SEQ ID NO:1791); miR-7150 (SEQ ID NO:1792); miR-7151 (SEQ ID NO:1793); miR-7152 (SEQ ID NO:1794); miR-7153 (SEQ ID NO:1795); miR-7154 (SEQ ID NO:1796); miR-7155 (SEQ ID NO:1797); miR-7156 (SEQ ID NO:1798); miR-7157 (SEQ ID NO:1799); miR-7158 (SEQ ID NO:1800); miR-7159 (SEQ ID NO:1801); miR-7160 (SEQ ID NO:1802); miR-7161 (SEQ ID NO:1803); miR-7162 (SEQ ID NO:1804); miR-7515 (SEQ ID NO:1805); miR-7641-2 (SEQ ID NO:1807); miR-7641-1 (SEQ ID NO:1806); miR-7702 (SEQ ID NO:1808); miR-7703 (SEQ ID NO:1809); miR-7704 (SEQ ID NO:1810); miR-7705 (SEQ ID NO:1811); miR-7706 (SEQ ID NO:1812); miR-7843 (SEQ ID NO:1813); miR-7844 (SEQ ID NO:1814); miR-7845 (SEQ ID NO:1815); miR-7846 (SEQ ID NO:1816); miR-7847 (SEQ ID NO:1817); miR-7848 (SEQ ID NO:1818); miR-7849 (SEQ ID NO:1819); miR-7850 (SEQ ID NO:1820); miR-7851 (SEQ ID NO:1821); miR-7852 (SEQ ID NO:1822); miR-7853 (SEQ ID NO:1823); miR-7854 (SEQ ID NO:1824); miR-7855 (SEQ ID NO:1825); miR-7856 (SEQ ID NO:1826); miR-7973-2 (SEQ ID NO:1828); miR-7973-1 (SEQ ID NO:1827); miR-7974 (SEQ ID NO:1829); miR-7975 (SEQ ID NO:1830); miR-7976 (SEQ ID NO:1831); miR-7977 (SEQ ID NO:1832); miR-7978 (SEQ ID NO:1833); miR-8052 (SEQ ID NO:1834); miR-8053 (SEQ ID NO:1835); miR-8054 (SEQ ID NO:1836); miR-8055 (SEQ ID NO:1837); miR-8056 (SEQ ID NO:1838); miR-8057 (SEQ ID NO:1839); miR-8058 (SEQ ID NO:1840); miR-8059 (SEQ ID NO:1841); miR-8060 (SEQ ID NO:1842); miR-8061 (SEQ ID NO:1843); miR-8062 (SEQ ID NO:1844); miR-8063 (SEQ ID NO:1845); miR-8064 (SEQ ID NO:1846); miR-8065 (SEQ ID NO:1847); miR-8066 (SEQ ID NO:1848); miR-8067 (SEQ ID NO:1849); miR-8068 (SEQ ID NO:1850); miR-8069 (SEQ ID NO:1851); miR-8070 (SEQ ID NO:1852); miR-8071-2 (SEQ ID NO:1854); miR-8071-1 (SEQ ID NO:1853); miR-8072 (SEQ ID NO:1855); miR-8073 (SEQ ID NO:1856); miR-8074 (SEQ ID NO:1857); miR-8075 (SEQ ID NO:1858); miR-8076 (SEQ ID NO:1859); miR-8077 (SEQ ID NO:1860); miR-8078 (SEQ ID NO:1861); miR-8079 (SEQ ID NO:1862); miR-8080 (SEQ ID NO:1863); miR-8081 (SEQ ID NO:1864); miR-8082 (SEQ ID NO:1865); miR-8083 (SEQ ID NO:1866); miR-8084 (SEQ ID NO:1867); miR-8085 (SEQ ID NO:1868); miR-8086 (SEQ ID NO:1869); miR-8087 (SEQ ID NO:1870); miR-8088 (SEQ ID NO:1871); and miR-8089 (SEQ ID NO:1872).

The following dog miRNA could be used: let-7a-1 (SEQ ID NO:2744); let-7a-2 (SEQ ID NO:2745); let-7b (SEQ ID NO:2746); let-7c (SEQ ID NO:2747); let-7e (SEQ ID NO:2748); let-7f (SEQ ID NO:2749); let-7g (SEQ ID NO:2750); let-7j (SEQ ID NO:2751); miR-1-1 (SEQ ID NO:2752); miR-1-2 (SEQ ID NO:2753); miR-7-1 (SEQ ID NO:2754); miR-7-2 (SEQ ID NO:2755); miR-7-3 (SEQ ID NO:2756); miR-9-1 (SEQ ID NO:2757); miR-9-2 (SEQ ID NO:2758); miR-9-3 (SEQ ID NO:2759); miR-10a (SEQ ID NO:2760); miR-10b (SEQ ID NO:2761); miR-15a (SEQ ID NO:2762); miR-15b (SEQ ID NO:2763); miR-16-1 (SEQ ID NO:2764); miR-16-2 (SEQ ID NO:2765); miR-17 (SEQ ID NO:2766); miR-18a (SEQ ID NO:2767); miR-18b (SEQ ID NO:2768); miR-19a (SEQ ID NO:2769); miR-19b-1 (SEQ ID NO:2770); miR-19b-2 (SEQ ID NO:2771); miR-20a (SEQ ID NO:2772); miR-20b (SEQ ID NO:2773); miR-21 (SEQ ID NO:2774); miR-22 (SEQ ID NO:2775); miR-23a (SEQ ID NO:2776); miR-23b (SEQ ID NO:2777); miR-24-1 (SEQ ID NO:2778); miR-24-2 (SEQ ID NO:2779); miR-25 (SEQ ID NO:2780); miR-26a-1 (SEQ ID NO:2781); miR-26a-2 (SEQ ID NO:2782); miR-26b (SEQ ID NO:2783); miR-27a (SEQ ID NO:2784); miR-27b (SEQ ID NO:2785); miR-28 (SEQ ID NO:2786); miR-29a (SEQ ID NO:2787); miR-29b-1 (SEQ ID NO:2788); miR-29b-2 (SEQ ID NO:2789); miR-29c-1 (SEQ ID NO:2790); miR-29c-2 (SEQ ID NO:2791); miR-30a (SEQ ID NO:2792); miR-30b (SEQ ID NO:2793); miR-30c-1 (SEQ ID NO:2794); miR-30c-2 (SEQ ID NO:2795); miR-30d (SEQ ID NO:2796); miR-30e (SEQ ID NO:2797); miR-31 (SEQ ID NO:2798); miR-32 (SEQ ID NO:2799); miR-33a (SEQ ID NO:2800); miR-33b (SEQ ID NO:2801); miR-34a (SEQ ID NO:2802); miR-34b (SEQ ID NO:2803); miR-34c (SEQ ID NO:2804); miR-92a-1 (SEQ ID NO:2805); miR-92a-2 (SEQ ID NO:2806); miR-92b (SEQ ID NO:2807); miR-93 (SEQ ID NO:2808); miR-95 (SEQ ID NO:2809); miR-96 (SEQ ID NO:2810); miR-98 (SEQ ID NO:2811); miR-99a-1 (SEQ ID NO:2812); miR-99a-2 (SEQ ID NO:2813); miR-99b (SEQ ID NO:2814); miR-101-1 (SEQ ID NO:2815); miR-101-2 (SEQ ID NO:2816); miR-103-1 (SEQ ID NO:2817); miR-103-2 (SEQ ID NO:2818); miR-105a (SEQ ID NO:2819); miR-105b (SEQ ID NO:2820); miR-106a (SEQ ID NO:2821); miR-106b (SEQ ID NO:2822); miR-107 (SEQ ID NO:2823); miR-122 (SEQ ID NO:2824); miR-124-1 (SEQ ID NO:2825); miR-124-2 (SEQ ID NO:2826); miR-124-3 (SEQ ID NO:2827); miR-125a (SEQ ID NO:2828); miR-125b-1 (SEQ ID NO:2829); miR-125b-2 (SEQ ID NO:2830); miR-126 (SEQ ID NO:2831); miR-127 (SEQ ID NO:2832); miR-128-1 (SEQ ID NO:2833); miR-128-2 (SEQ ID NO:2834); miR-129-1 (SEQ ID NO:2835); miR-129-2 (SEQ ID NO:2836); miR-130a (SEQ ID NO:2837); miR-130b (SEQ ID NO:2838); miR-132 (SEQ ID NO:2839); miR-133a (SEQ ID NO:2840); miR-133b (SEQ ID NO:2841); miR-133c (SEQ ID NO:2842); miR-134 (SEQ ID NO:2843); miR-135a-1 (SEQ ID NO:2844); miR-135a-2 (SEQ ID NO:2845); miR-135b (SEQ ID NO:2846); miR-136 (SEQ ID NO:2847); miR-137 (SEQ ID NO:2848); miR-138a (SEQ ID NO:2849); miR-138b (SEQ ID NO:2850); miR-139 (SEQ ID NO:2851); miR-140 (SEQ ID NO:2852); miR-141 (SEQ ID NO:2853); miR-142 (SEQ ID NO:2854); miR-143 (SEQ ID NO:2855); miR-144 (SEQ ID NO:2856); miR-145 (SEQ ID NO:2857); miR-146a (SEQ ID NO:2858); miR-146b (SEQ ID NO:2859); miR-147 (SEQ ID NO:2860); miR-148a (SEQ ID NO:2861); miR-148b (SEQ ID NO:2862); miR-149 (SEQ ID NO:2863); miR-150 (SEQ ID NO:2864); miR-151 (SEQ ID NO:2865); miR-152 (SEQ ID NO:2866); miR-153 (SEQ ID NO:2867); miR-155 (SEQ ID NO:2868); miR-181a-1 (SEQ ID NO:2869); miR-181a-2 (SEQ ID NO:2870); miR-181b-1 (SEQ ID NO:2871); miR-181b-2 (SEQ ID NO:2872); miR-181c (SEQ ID NO:2873); miR-181d (SEQ ID NO:2874); miR-182 (SEQ ID NO:2875); miR-183 (SEQ ID NO:2876); miR-184 (SEQ ID NO:2877); miR-185 (SEQ ID NO:2878); miR-186 (SEQ ID NO:2879); miR-187 (SEQ ID NO:2880); miR-188 (SEQ ID NO:2881); miR-190a (SEQ ID NO:2882); miR-190b (SEQ ID NO:2883); miR-191 (SEQ ID NO:2884); miR-192 (SEQ ID NO:2885); miR-193a (SEQ ID NO:2886); miR-193b (SEQ ID NO:2887); miR-194 (SEQ ID NO:2888); miR-195 (SEQ ID NO:2889); miR-196a-1 (SEQ ID NO:2890); miR-196a-2 (SEQ ID NO:2891); miR-196b (SEQ ID NO:2892); miR-197 (SEQ ID NO:2893); miR-199-1 (SEQ ID NO:2894); miR-199-2 (SEQ ID NO:2895); miR-199-3 (SEQ ID NO:2896); miR-200a (SEQ ID NO:2897); miR-200b (SEQ ID NO:2898); miR-200c (SEQ ID NO:2899); miR-202 (SEQ ID NO:2900); miR-203 (SEQ ID NO:2901); miR-204 (SEQ ID NO:2902); miR-205 (SEQ ID NO:2903); miR-206 (SEQ ID NO:2904); miR-207 (SEQ ID NO:2905); miR-208a (SEQ ID NO:2906); miR-208b (SEQ ID NO:2907); miR-210 (SEQ ID NO:2908); miR-211 (SEQ ID NO:2909); miR-212 (SEQ ID NO:2910); miR-214 (SEQ ID NO:2911); miR-215 (SEQ ID NO:2912); miR-216a (SEQ ID NO:2913); miR-216b (SEQ ID NO:2914); miR-217 (SEQ ID NO:2915); miR-218-1 (SEQ ID NO:2916); miR-218-2 (SEQ ID NO:2917); miR-219-1 (SEQ ID NO:2918); miR-219-2 (SEQ ID NO:2919); miR-221 (SEQ ID NO:2920); miR-222 (SEQ ID NO:2921); miR-223 (SEQ ID NO:2922); miR-224 (SEQ ID NO:2923); miR-299 (SEQ ID NO:2924); miR-300 (SEQ ID NO:2925); miR-301a (SEQ ID NO:2926); miR-301b (SEQ ID NO:2927); miR-302a (SEQ ID NO:2928); miR-302b (SEQ ID NO:2929); miR-302c (SEQ ID NO:2930); miR-302d (SEQ ID NO:2931); miR-320 (SEQ ID NO:2932); miR-323 (SEQ ID NO:2933); miR-324 (SEQ ID NO:2934); miR-325 (SEQ ID NO:2935); miR-326 (SEQ ID NO:2936); miR-328 (SEQ ID NO:2937); miR-329a (SEQ ID NO:2938); miR-329b (SEQ ID NO:2939); miR-330 (SEQ ID NO:2940); miR-331 (SEQ ID NO:2941); miR-335 (SEQ ID NO:2942); miR-338 (SEQ ID NO:2943); miR-340 (SEQ ID NO:2944); miR-342 (SEQ ID NO:2945); miR-345 (SEQ ID NO:2946); miR-346 (SEQ ID NO:2947); miR-350 (SEQ ID NO:2948); miR-361 (SEQ ID NO:2949); miR-362 (SEQ ID NO:2950); miR-363 (SEQ ID NO:2951); miR-365-1 (SEQ ID NO:2952); miR-365-2 (SEQ ID NO:2953); miR-367 (SEQ ID NO:2954); miR-369 (SEQ ID NO:2955); miR-370 (SEQ ID NO:2956); miR-371 (SEQ ID NO:2957); miR-374a (SEQ ID NO:2958); miR-374b (SEQ ID NO:2959); miR-375 (SEQ ID NO:2960); miR-376a-1 (SEQ ID NO:2961); miR-376a-2 (SEQ ID NO:2962); miR-376a-3 (SEQ ID NO:2963); miR-376b (SEQ ID NO:2964); miR-376c (SEQ ID NO:2965); miR-377 (SEQ ID NO:2966); miR-378 (SEQ ID NO:2967); miR-379 (SEQ ID NO:2968); miR-380 (SEQ ID NO:2969); miR-381 (SEQ ID NO:2970); miR-382 (SEQ ID NO:2971); miR-383 (SEQ ID NO:2972); miR-384 (SEQ ID NO:2973); miR-409 (SEQ ID NO:2974); miR-410 (SEQ ID NO:2975); miR-411 (SEQ ID NO:2976); miR-421 (SEQ ID NO:2977); miR-423a (SEQ ID NO:2978); miR-424 (SEQ ID NO:2979); miR-425 (SEQ ID NO:2980); miR-429 (SEQ ID NO:2981); miR-432 (SEQ ID NO:2982); miR-433 (SEQ ID NO:2983); miR-448 (SEQ ID NO:2984); miR-449 (SEQ ID NO:2985); miR-450a (SEQ ID NO:2986); miR-450b (SEQ ID NO:2987); miR-451 (SEQ ID NO:2988); miR-452 (SEQ ID NO:2989); miR-454 (SEQ ID NO:2990); miR-455 (SEQ ID NO:2991); miR-483 (SEQ ID NO:2992); miR-485 (SEQ ID NO:2993); miR-487a (SEQ ID NO:2994); miR-487b (SEQ ID NO:2995); miR-488 (SEQ ID NO:2996); miR-489 (SEQ ID NO:2997); miR-490 (SEQ ID NO:2998); miR-491 (SEQ ID NO:2999); miR-493 (SEQ ID NO:3000); miR-494 (SEQ ID NO:3001); miR-495 (SEQ ID NO:3002); miR-496 (SEQ ID NO:3003); miR-497 (SEQ ID NO:3004); miR-499 (SEQ ID NO:3005); miR-500 (SEQ ID NO:3006); miR-502 (SEQ ID NO:3007); miR-503 (SEQ ID NO:3008); miR-504 (SEQ ID NO:3009); miR-505 (SEQ ID NO:3010); miR-514 (SEQ ID NO:3011); miR-532 (SEQ ID NO:3012); miR-539 (SEQ ID NO:3013); miR-542 (SEQ ID NO:3014); miR-543 (SEQ ID NO:3015); miR-544 (SEQ ID NO:3016); miR-545 (SEQ ID NO:3017); miR-551a (SEQ ID NO:3018); miR-551b (SEQ ID NO:3019); miR-568 (SEQ ID NO:3020); miR-574 (SEQ ID NO:3021); miR-578 (SEQ ID NO:3022); miR-582 (SEQ ID NO:3023); miR-589 (SEQ ID NO:3024); miR-590 (SEQ ID NO:3025); miR-592 (SEQ ID NO:3026); miR-599 (SEQ ID NO:3027); miR-615 (SEQ ID NO:3028); miR-628 (SEQ ID NO:3029); miR-631 (SEQ ID NO:3030); miR-632 (SEQ ID NO:3031); miR-652 (SEQ ID NO:3032); miR-653 (SEQ ID NO:3033); miR-660 (SEQ ID NO:3034); miR-664 (SEQ ID NO:3035); miR-665 (SEQ ID NO:3036); miR-671 (SEQ ID NO:3037); miR-676 (SEQ ID NO:3038); miR-708 (SEQ ID NO:3039); miR-718 (SEQ ID NO:3040); miR-758 (SEQ ID NO:3041); miR-759 (SEQ ID NO:3042); miR-761 (SEQ ID NO:3043); miR-764 (SEQ ID NO:3044); miR-802 (SEQ ID NO:3045); miR-872 (SEQ ID NO:3046); miR-874 (SEQ ID NO:3047); miR-875 (SEQ ID NO:3048); miR-876 (SEQ ID NO:3049); miR-885 (SEQ ID NO:3050); miR-1199 (SEQ ID NO:3051); miR-1271 (SEQ ID NO:3052); miR-1306 (SEQ ID NO:3053); miR-1307 (SEQ ID NO:3054); miR-1835 (SEQ ID NO:3055); miR-1836 (SEQ ID NO:3056); miR-1837-1 (SEQ ID NO:3057); miR-1837-2 (SEQ ID NO:3058); miR-1837-3 (SEQ ID NO:3059); miR-1837-4 (SEQ ID NO:3060); miR-1838 (SEQ ID NO:3061); miR-1839 (SEQ ID NO:3062); miR-1840 (SEQ ID NO:3063); miR-1841 (SEQ ID NO:3064); miR-1842 (SEQ ID NO:3065); miR-1843 (SEQ ID NO:3066); and miR-1844 (SEQ ID NO:3067).

The following horse miRNAs could be used: let-7a (SEQ ID NO:3068); let-7a-2 (SEQ ID NO:3069); let-7c (SEQ ID NO:3070); let-7d (SEQ ID NO:3071); let-7e (SEQ ID NO:3072); let-7f (SEQ ID NO:3073); let-7g (SEQ ID NO:3074); miR-1-1 (SEQ ID NO:3075); miR-1-2 (SEQ ID NO:3076); miR-7-1 (SEQ ID NO:3077); miR-7-2 (SEQ ID NO:3078); miR-7-3 (SEQ ID NO:3079); miR-9a (SEQ ID NO:3080); miR-9a-2 (SEQ ID NO:3081); miR-10a (SEQ ID NO:3082); miR-10b (SEQ ID NO:3083); miR-15a (SEQ ID NO:3084); miR-15b (SEQ ID NO:3085); miR-16-1 (SEQ ID NO:3086); miR-16-2 (SEQ ID NO:3087); miR-17 (SEQ ID NO:3088); miR-18a (SEQ ID NO:3089); miR-18b (SEQ ID NO:3090); miR-19a (SEQ ID NO:3091); miR-19b (SEQ ID NO:3092); miR-19b-2 (SEQ ID NO:3093); miR-20a (SEQ ID NO:3094); miR-20b (SEQ ID NO:3095); miR-21 (SEQ ID NO:3096); miR-22 (SEQ ID NO:3097); miR-23a (SEQ ID NO:3098); miR-23b (SEQ ID NO:3099); miR-24-1 (SEQ ID NO:3100); miR-24-2 (SEQ ID NO:3101); miR-25 (SEQ ID NO:3102); miR-26a (SEQ ID NO:3103); miR-26a-2 (SEQ ID NO:3104); miR-27a (SEQ ID NO:3105); miR-27b (SEQ ID NO:3106); miR-28 (SEQ ID NO:3107); miR-29a (SEQ ID NO:3108); miR-29b (SEQ ID NO:3109); miR-29b-2 (SEQ ID NO:3110); miR-29c (SEQ ID NO:3111); miR-29c-2 (SEQ ID NO:3112); miR-30b (SEQ ID NO:3113); miR-30c (SEQ ID NO:3114); miR-30c-2 (SEQ ID NO:3115); miR-30d (SEQ ID NO:3116); miR-30e (SEQ ID NO:3117); miR-31 (SEQ ID NO:3118); miR-32 (SEQ ID NO:3119); miR-33a (SEQ ID NO:3120); miR-33b (SEQ ID NO:3121); miR-34a (SEQ ID NO:3122); miR-34b (SEQ ID NO:3123); miR-34c (SEQ ID NO:3124); miR-92a (SEQ ID NO:3125); miR-92a-2 (SEQ ID NO:3126); miR-92b (SEQ ID NO:3127); miR-93 (SEQ ID NO:3128); miR-95 (SEQ ID NO:3129); miR-96 (SEQ ID NO:3130); miR-98 (SEQ ID NO:3131); miR-99a-2 (SEQ ID NO:3132); miR-99b (SEQ ID NO:3133); miR-100 (SEQ ID NO:3134); miR-101-1 (SEQ ID NO:3135); miR-101-2 (SEQ ID NO:3136); miR-103 (SEQ ID NO:3137); miR-105 (SEQ ID NO:3138); miR-106a (SEQ ID NO:3139); miR-106b (SEQ ID NO:3140); miR-107a (SEQ ID NO:3141); miR-107b (SEQ ID NO:3142); miR-122 (SEQ ID NO:3143); miR-124-1 (SEQ ID NO:3144); miR-124-2 (SEQ ID NO:3145); miR-125a (SEQ ID NO:3146); miR-125b (SEQ ID NO:3147); miR-125b-2 (SEQ ID NO:3148); miR-126 (SEQ ID NO:3149); miR-127 (SEQ ID NO:3150); miR-128-1 (SEQ ID NO:3151); miR-128-2 (SEQ ID NO:3152); miR-129a (SEQ ID NO:3153); miR-129b (SEQ ID NO:3154); miR-130a (SEQ ID NO:3155); miR-130b (SEQ ID NO:3156); miR-132 (SEQ ID NO:3157); miR-133a (SEQ ID NO:3158); miR-133a-2 (SEQ ID NO:3159); miR-133b (SEQ ID NO:3160); miR-134 (SEQ ID NO:3161); miR-135a (SEQ ID NO:3162); miR-135a-2 (SEQ ID NO:3163); miR-135b (SEQ ID NO:3164); miR-136 (SEQ ID NO:3165); miR-137 (SEQ ID NO:3166); miR-138-1 (SEQ ID NO:3167); miR-138-2 (SEQ ID NO:3168); miR-139 (SEQ ID NO:3169); miR-140 (SEQ ID NO:3170); miR-141 (SEQ ID NO:3171); miR-142 (SEQ ID NO:3172); miR-143 (SEQ ID NO:3173); miR-144 (SEQ ID NO:3174); miR-145 (SEQ ID NO:3175); miR-146a (SEQ ID NO:3176); miR-146b (SEQ ID NO:3177); miR-147b (SEQ ID NO:3178); miR-148a (SEQ ID NO:3179); miR-148b (SEQ ID NO:3180); miR-149 (SEQ ID NO:3181); miR-150 (SEQ ID NO:3182); miR-151 (SEQ ID NO:3183); miR-153-1 (SEQ ID NO:3184); miR-153-2 (SEQ ID NO:3185); miR-154 (SEQ ID NO:3186); miR-155 (SEQ ID NO:3187); miR-181a (SEQ ID NO:3188); miR-181a-2 (SEQ ID NO:3189); miR-181b (SEQ ID NO:3190); miR-182 (SEQ ID NO:3191); miR-183 (SEQ ID NO:3192); miR-184 (SEQ ID NO:3193); miR-186 (SEQ ID NO:3194); miR-187 (SEQ ID NO:3195); miR-188 (SEQ ID NO:3196); miR-190a (SEQ ID NO:3197); miR-190b (SEQ ID NO:3198); miR-191 (SEQ ID NO:3199); miR-192 (SEQ ID NO:3200); miR-193a (SEQ ID NO:3201); miR-193b (SEQ ID NO:3202); miR-194-1 (SEQ ID NO:3203); miR-194-2 (SEQ ID NO:3204); miR-195 (SEQ ID NO:3205); miR-196a (SEQ ID NO:3206); miR-196b (SEQ ID NO:3207); miR-197 (SEQ ID NO:3208); miR-199a (SEQ ID NO:3209); miR-199b (SEQ ID NO:3210); miR-200a (SEQ ID NO:3211); miR-200b (SEQ ID NO:3212); miR-200c (SEQ ID NO:3213); miR-204b-2 (SEQ ID NO:3214); miR-205 (SEQ ID NO:3215); miR-206-2 (SEQ ID NO:3216); miR-208a (SEQ ID NO:3217); miR-208b (SEQ ID NO:3218); miR-211 (SEQ ID NO:3219); miR-212 (SEQ ID NO:3220); miR-214 (SEQ ID NO:3221); miR-215 (SEQ ID NO:3222); miR-216a (SEQ ID NO:3223); miR-216b (SEQ ID NO:3224); miR-217 (SEQ ID NO:3225); miR-218-1 (SEQ ID NO:3226); miR-218-2 (SEQ ID NO:3227); miR-219-1 (SEQ ID NO:3228); miR-219-2 (SEQ ID NO:3229); miR-221 (SEQ ID NO:3230); miR-222 (SEQ ID NO:3231); miR-223 (SEQ ID NO:3232); miR-224 (SEQ ID NO:3233); miR-296 (SEQ ID NO:3234); miR-299 (SEQ ID NO:3235); miR-301a (SEQ ID NO:3236); miR-301b (SEQ ID NO:3237); miR-302a (SEQ ID NO:3238); miR-302b (SEQ ID NO:3239); miR-302c (SEQ ID NO:3240); miR-302d (SEQ ID NO:3241); miR-323 (SEQ ID NO:3242); miR-324 (SEQ ID NO:3243); miR-326 (SEQ ID NO:3244); miR-328 (SEQ ID NO:3245); miR-329 (SEQ ID NO:3246); miR-330 (SEQ ID NO:3247); miR-331 (SEQ ID NO:3248); miR-335 (SEQ ID NO:3249); miR-337 (SEQ ID NO:3250); miR-338 (SEQ ID NO:3251); miR-340 (SEQ ID NO:3252); miR-342 (SEQ ID NO:3253); miR-345 (SEQ ID NO:3254); miR-346 (SEQ ID NO:3255); miR-350 (SEQ ID NO:3256); miR-361 (SEQ ID NO:3257); miR-362 (SEQ ID NO:3258); miR-363 (SEQ ID NO:3259); miR-365-1 (SEQ ID NO:3260); miR-365-2 (SEQ ID NO:3261); miR-367 (SEQ ID NO:3262); miR-369 (SEQ ID NO:3263); miR-370 (SEQ ID NO:3264); miR-371 (SEQ ID NO:3265); miR-374a (SEQ ID NO:3266); miR-374b (SEQ ID NO:3267); miR-376a (SEQ ID NO:3268); miR-376b (SEQ ID NO:3269); miR-376c (SEQ ID NO:3270); miR-377 (SEQ ID NO:3271); miR-378 (SEQ ID NO:3272); miR-379 (SEQ ID NO:3273); miR-380 (SEQ ID NO:3274); miR-381 (SEQ ID NO:3275); miR-382 (SEQ ID NO:3276); miR-383 (SEQ ID NO:3277); miR-384 (SEQ ID NO:3278); miR-409 (SEQ ID NO:3279); miR-410 (SEQ ID NO:3280); miR-411 (SEQ ID NO:3281); miR-412 (SEQ ID NO:3282); miR-421 (SEQ ID NO:3283); miR-423 (SEQ ID NO:3284); miR-424 (SEQ ID NO:3285); miR-429 (SEQ ID NO:3286); miR-431 (SEQ ID NO:3287); miR-432 (SEQ ID NO:3288); miR-433 (SEQ ID NO:3289); miR-448 (SEQ ID NO:3290); miR-449a (SEQ ID NO:3291); miR-450a (SEQ ID NO:3292); miR-450b (SEQ ID NO:3293); miR-450c (SEQ ID NO:3294); miR-451 (SEQ ID NO:3295); miR-454 (SEQ ID NO:3296); miR-485 (SEQ ID NO:3297); miR-486 (SEQ ID NO:3298); miR-487a (SEQ ID NO:3299); miR-487b (SEQ ID NO:3300); miR-488 (SEQ ID NO:3301); miR-489 (SEQ ID NO:3302); miR-490 (SEQ ID NO:3303); miR-491 (SEQ ID NO:3304); miR-492-1 (SEQ ID NO:3305); miR-492-2 (SEQ ID NO:3306); miR-493a (SEQ ID NO:3307); miR-493b (SEQ ID NO:3308); miR-494 (SEQ ID NO:3309); miR-495 (SEQ ID NO:3310); miR-496 (SEQ ID NO:3311); miR-497 (SEQ ID NO:3312); miR-499 (SEQ ID NO:3313); miR-500-1 (SEQ ID NO:3314); miR-500-2 (SEQ ID NO:3315); miR-501 (SEQ ID NO:3316); miR-502 (SEQ ID NO:3317); miR-503 (SEQ ID NO:3318); miR-504 (SEQ ID NO:3319); miR-505 (SEQ ID NO:3320); miR-507 (SEQ ID NO:3321); miR-508 (SEQ ID NO:3322); miR-509 (SEQ ID NO:3323); miR-514 (SEQ ID NO:3324); miR-532 (SEQ ID NO:3325); miR-539 (SEQ ID NO:3326); miR-541 (SEQ ID NO:3327); miR-542 (SEQ ID NO:3328); miR-543 (SEQ ID NO:3329); miR-544-2 (SEQ ID NO:3330); miR-544b (SEQ ID NO:3331); miR-545 (SEQ ID NO:3332); miR-551a (SEQ ID NO:3333); miR-551b (SEQ ID NO:3334); miR-568 (SEQ ID NO:3335); miR-582 (SEQ ID NO:3336); miR-590 (SEQ ID NO:3337); miR-592 (SEQ ID NO:3338); miR-598 (SEQ ID NO:3339); miR-615 (SEQ ID NO:3340); miR-628a (SEQ ID NO:3341); miR-632 (SEQ ID NO:3342); miR-652 (SEQ ID NO:3343); miR-653 (SEQ ID NO:3344); miR-655 (SEQ ID NO:3345); miR-656 (SEQ ID NO:3346); miR-660 (SEQ ID NO:3347); miR-664 (SEQ ID NO:3348); miR-670 (SEQ ID NO:3349); miR-671 (SEQ ID NO:3350); miR-672 (SEQ ID NO:3351); miR-675 (SEQ ID NO:3352); miR-684 (SEQ ID NO:3353); miR-703 (SEQ ID NO:3354); miR-708 (SEQ ID NO:3355); miR-711 (SEQ ID NO:3356); miR-758 (SEQ ID NO:3357); miR-761 (SEQ ID NO:3358); miR-763 (SEQ ID NO:3359); miR-764 (SEQ ID NO:3360); miR-767 (SEQ ID NO:3361); miR-769a (SEQ ID NO:3362); miR-769b (SEQ ID NO:3363); miR-770 (SEQ ID NO:3364); miR-802 (SEQ ID NO:3365); miR-872 (SEQ ID NO:3366); miR-873 (SEQ ID NO:3367); miR-874 (SEQ ID NO:3368); miR-876 (SEQ ID NO:3369); miR-885 (SEQ ID NO:3370); miR-889 (SEQ ID NO:3371); miR-1179 (SEQ ID NO:3372); miR-1180 (SEQ ID NO:3373); miR-1185 (SEQ ID NO:3374); miR-1193 (SEQ ID NO:3375); miR-1197 (SEQ ID NO:3376); miR-1204 (SEQ ID NO:3377); miR-1244 (SEQ ID NO:3378); miR-1248 (SEQ ID NO:3379); miR-1255b (SEQ ID NO:3380); miR-1261 (SEQ ID NO:3381); miR-1264 (SEQ ID NO:3382); miR-1271 (SEQ ID NO:3383); miR-1282 (SEQ ID NO:3384); miR-1289 (SEQ ID NO:3385); miR-1291a (SEQ ID NO:3386); miR-1291b (SEQ ID NO:3387); miR-1296 (SEQ ID NO:3388); miR-1298 (SEQ ID NO:3389); miR-1301 (SEQ ID NO:3390); miR-1302-1 (SEQ ID NO:3391); miR-1302b-2 (SEQ ID NO:3392); miR-1302c-5 (SEQ ID NO:3393); miR-1302d-4 (SEQ ID NO:3394); miR-1302e-6 (SEQ ID NO:3395); miR-1302e-7 (SEQ ID NO:3396); miR-1461 (SEQ ID NO:3397); miR-1468 (SEQ ID NO:3398); miR-1597 (SEQ ID NO:3399); miR-1839 (SEQ ID NO:3400); miR-1842 (SEQ ID NO:3401); miR-1892 (SEQ ID NO:3402); miR-1898 (SEQ ID NO:3403); miR-1902 (SEQ ID NO:3404); miR-1905a (SEQ ID NO:3405); miR-1905b (SEQ ID NO:3406); miR-1905c (SEQ ID NO:3407); and miR-1912 (SEQ ID NO:3408).

The following mouse miRNAs could be used: let-7a-1 (SEQ ID NO:3409); let-7a-2 (SEQ ID NO:3410); let-7b (SEQ ID NO:3411); let-7c-1 (SEQ ID NO:3412); let-7c-2 (SEQ ID NO:3413); let-7d (SEQ ID NO:3414); let-7e (SEQ ID NO:3415); let-7f-1 (SEQ ID NO:3416); let-7f-2 (SEQ ID NO:3417); let-7g (SEQ ID NO:3418); let-7i (SEQ ID NO:3419); let-7j (SEQ ID NO:3420); let-7k (SEQ ID NO:3421); miR-1a-1 (SEQ ID NO:3422); miR-1a-2 (SEQ ID NO:3423); miR-1b (SEQ ID NO:3424); miR-7a-1 (SEQ ID NO:3425); miR-7a-2 (SEQ ID NO:3426); miR-7b (SEQ ID NO:3427); miR-9-1 (SEQ ID NO:3428); miR-9-2 (SEQ ID NO:3429); miR-9-3 (SEQ ID NO:3430); miR-10a (SEQ ID NO:3431); miR-10b (SEQ ID NO:3432); miR-15a (SEQ ID NO:3433); miR-15b (SEQ ID NO:3434); miR-16-1 (SEQ ID NO:3435); miR-16-2 (SEQ ID NO:3436); miR-17 (SEQ ID NO:3437); miR-18a (SEQ ID NO:3438); miR-18b (SEQ ID NO:3439); miR-19a (SEQ ID NO:3440); miR-19b-1 (SEQ ID NO:3441); miR-19b-2 (SEQ ID NO:3442); miR-20a (SEQ ID NO:3443); miR-20b (SEQ ID NO:3444); miR-21a (SEQ ID NO:3445); miR-21b (SEQ ID NO:3446); miR-21c (SEQ ID NO:3447); miR-22 (SEQ ID NO:3448); miR-23a (SEQ ID NO:3449); miR-23b (SEQ ID NO:3450); miR-24-1 (SEQ ID NO:3451); miR-24-2 (SEQ ID NO:3452); miR-25 (SEQ ID NO:3453); miR-26a-1 (SEQ ID NO:3454); miR-26a-2 (SEQ ID NO:3455); miR-26b (SEQ ID NO:3456); miR-27a (SEQ ID NO:3457); miR-27b (SEQ ID NO:3458); miR-28a (SEQ ID NO:3459); miR-28b (SEQ ID NO:3460); miR-28c (SEQ ID NO:3461); miR-29a (SEQ ID NO:3462); miR-29b-1 (SEQ ID NO:3463); miR-29b-2 (SEQ ID NO:3464); miR-29c (SEQ ID NO:3465); miR-30a (SEQ ID NO:3466); miR-30b (SEQ ID NO:3467); miR-30c-1 (SEQ ID NO:3468); miR-30c-2 (SEQ ID NO:3469); miR-30d (SEQ ID NO:3470); miR-30e (SEQ ID NO:3471); miR-30f (SEQ ID NO:3472); miR-31 (SEQ ID NO:3473); miR-32 (SEQ ID NO:3474); miR-33 (SEQ ID NO:3475); miR-34a (SEQ ID NO:3476); miR-34b (SEQ ID NO:3477); miR-34c (SEQ ID NO:3478); miR-92a-1 (SEQ ID NO:3479); miR-92a-2 (SEQ ID NO:3480); miR-92b (SEQ ID NO:3481); miR-93 (SEQ ID NO:3482); miR-96 (SEQ ID NO:3483); miR-98 (SEQ ID NO:3484); miR-99a (SEQ ID NO:3485); miR-99b (SEQ ID NO:3486); miR-100 (SEQ ID NO:3487); miR-101a (SEQ ID NO:3488); miR-101b (SEQ ID NO:3489); miR-101c (SEQ ID NO:3490); miR-103-1 (SEQ ID NO:3491); miR-103-2 (SEQ ID NO:3492); miR-105 (SEQ ID NO:3493); miR-106a (SEQ ID NO:3494); miR-106b (SEQ ID NO:3495); miR-107 (SEQ ID NO:3496); miR-122 (SEQ ID NO:3497); miR-124-1 (SEQ ID NO:3498); miR-124-2 (SEQ ID NO:3499); miR-124-3 (SEQ ID NO:3500); miR-125a (SEQ ID NO:3501); miR-125b-1 (SEQ ID NO:3502); miR-125b-2 (SEQ ID NO:3503); miR-126a (SEQ ID NO:3504); miR-126b (SEQ ID NO:3505); miR-127 (SEQ ID NO:3506); miR-128-1 (SEQ ID NO:3507); miR-128-2 (SEQ ID NO:3508); miR-129-1 (SEQ ID NO:3509); miR-129-2 (SEQ ID NO:3510); miR-129b (SEQ ID NO:3511); miR-130a (SEQ ID NO:3512); miR-130b (SEQ ID NO:3513); miR-130c (SEQ ID NO:3514); miR-132 (SEQ ID NO:3515); miR-133a-1 (SEQ ID NO:3516); miR-133a-2 (SEQ ID NO:3517); miR-133b (SEQ ID NO:3518); miR-133c (SEQ ID NO:3519); miR-134 (SEQ ID NO:3520); miR-135a-1 (SEQ ID NO:3521); miR-135a-2 (SEQ ID NO:3522); miR-135b (SEQ ID NO:3523); miR-136 (SEQ ID NO:3524); miR-137 (SEQ ID NO:3525); miR-138-1 (SEQ ID NO:3526); miR-138-2 (SEQ ID NO:3527); miR-139 (SEQ ID NO:3528); miR-140 (SEQ ID NO:3529); miR-141 (SEQ ID NO:3530); miR-142 (SEQ ID NO:3531); miR-142b (SEQ ID NO:3532); miR-143 (SEQ ID NO:3533); miR-144 (SEQ ID NO:3534); miR-145a (SEQ ID NO:3535); miR-145b (SEQ ID NO:3536); miR-146a (SEQ ID NO:3537); miR-146b (SEQ ID NO:3538); miR-147 (SEQ ID NO:3539); miR-148a (SEQ ID NO:3540); miR-148b (SEQ ID NO:3541); miR-149 (SEQ ID NO:3542); miR-150 (SEQ ID NO:3543); miR-151 (SEQ ID NO:3544); miR-152 (SEQ ID NO:3545); miR-153 (SEQ ID NO:3546); miR-154 (SEQ ID NO:3547); miR-155 (SEQ ID NO:3548); miR-181a-1 (SEQ ID NO:3549); miR-181a-2 (SEQ ID NO:3550); miR-181b-1 (SEQ ID NO:3551); miR-181b-2 (SEQ ID NO:3552); miR-181c (SEQ ID NO:3553); miR-181d (SEQ ID NO:3554); miR-182 (SEQ ID NO:3555); miR-183 (SEQ ID NO:3556); miR-184 (SEQ ID NO:3557); miR-185 (SEQ ID NO:3558); miR-186 (SEQ ID NO:3559); miR-187 (SEQ ID NO:3560); miR-188 (SEQ ID NO:3561); miR-190a (SEQ ID NO:3562); miR-190b (SEQ ID NO:3563); miR-191 (SEQ ID NO:3564); miR-192 (SEQ ID NO:3565); miR-193a (SEQ ID NO:3566); miR-193b (SEQ ID NO:3567); miR-194-1 (SEQ ID NO:3568); miR-194-2 (SEQ ID NO:3569); miR-195a (SEQ ID NO:3570); miR-195b (SEQ ID NO:3571); miR-196a-1 (SEQ ID NO:3572); miR-196a-2 (SEQ ID NO:3573); miR-196b (SEQ ID NO:3574); miR-199a-1 (SEQ ID NO:3575); miR-199a-2 (SEQ ID NO:3576); miR-199b (SEQ ID NO:3577); miR-200a (SEQ ID NO:3578); miR-200b (SEQ ID NO:3579); miR-200c (SEQ ID NO:3580); miR-201 (SEQ ID NO:3581); miR-202 (SEQ ID NO:3582); miR-203 (SEQ ID NO:3583); miR-204 (SEQ ID NO:3584); miR-205 (SEQ ID NO:3585); miR-206 (SEQ ID NO:3586); miR-207 (SEQ ID NO:3587); miR-208a (SEQ ID NO:3588); miR-208b (SEQ ID NO:3589); miR-210 (SEQ ID NO:3590); miR-211 (SEQ ID NO:3591); miR-212 (SEQ ID NO:3592); miR-214 (SEQ ID NO:3593); miR-215 (SEQ ID NO:3594); miR-216a (SEQ ID NO:3595); miR-216b (SEQ ID NO:3596); miR-216c (SEQ ID NO:3597); miR-217 (SEQ ID NO:3598); miR-218-1 (SEQ ID NO:3599); miR-218-2 (SEQ ID NO:3600); miR-219a-1 (SEQ ID NO:3601); miR-219a-2 (SEQ ID NO:3602); miR-219b (SEQ ID NO:3603); miR-219c (SEQ ID NO:3604); miR-221 (SEQ ID NO:3605); miR-222 (SEQ ID NO:3606); miR-223 (SEQ ID NO:3607); miR-224 (SEQ ID NO:3608); miR-290a (SEQ ID NO:3609); miR-290b (SEQ ID NO:3610); miR-291a (SEQ ID NO:3611); miR-291b (SEQ ID NO:3612); miR-292 (SEQ ID NO:3613); miR-292b (SEQ ID NO:3614); miR-293 (SEQ ID NO:3615); miR-294 (SEQ ID NO:3616); miR-295 (SEQ ID NO:3617); miR-296 (SEQ ID NO:3618); miR-297a-1 (SEQ ID NO:3619); miR-297a-2 (SEQ ID NO:3620); miR-297a-3 (SEQ ID NO:3621); miR-297a-4 (SEQ ID NO:3622); miR-297b (SEQ ID NO:3623); miR-297c (SEQ ID NO:3624); miR-298 (SEQ ID NO:3625); miR-299a (SEQ ID NO:3626); miR-299b (SEQ ID NO:3627); miR-300 (SEQ ID NO:3628); miR-301a (SEQ ID NO:3629); miR-301b (SEQ ID NO:3630); miR-302a (SEQ ID NO:3631); miR-302b (SEQ ID NO:3632); miR-302c (SEQ ID NO:3633); miR-302d (SEQ ID NO:3634); miR-320 (SEQ ID NO:3635); miR-322 (SEQ ID NO:3636); miR-323 (SEQ ID NO:3637); miR-324 (SEQ ID NO:3638); miR-325 (SEQ ID NO:3639); miR-326 (SEQ ID NO:3640); miR-327 (SEQ ID NO:3641); miR-328 (SEQ ID NO:3642); miR-329 (SEQ ID NO:3643); miR-330 (SEQ ID NO:3644); miR-331 (SEQ ID NO:3645); miR-335 (SEQ ID NO:3646); miR-337 (SEQ ID NO:3647); miR-338 (SEQ ID NO:3648); miR-339 (SEQ ID NO:3649); miR-340 (SEQ ID NO:3650); miR-341 (SEQ ID NO:3651); miR-342 (SEQ ID NO:3652); miR-343 (SEQ ID NO:3653); miR-344-1 (SEQ ID NO:3654); miR-344-2 (SEQ ID NO:3655); miR-344b (SEQ ID NO:3656); miR-344c (SEQ ID NO:3657); miR-344d-1 (SEQ ID NO:3658); miR-344d-2 (SEQ ID NO:3659); miR-344d-3 (SEQ ID NO:3660); miR-344e (SEQ ID NO:3661); miR-344f (SEQ ID NO:3662); miR-344g (SEQ ID NO:3663); miR-344h-1 (SEQ ID NO:3664); miR-344h-2 (SEQ ID NO:3665); miR-344i (SEQ ID NO:3666); miR-345 (SEQ ID NO:3667); miR-346 (SEQ ID NO:3668); miR-350 (SEQ ID NO:3669); miR-351 (SEQ ID NO:3670); miR-361 (SEQ ID NO:3671); miR-362 (SEQ ID NO:3672); miR-363 (SEQ ID NO:3673); miR-365-1 (SEQ ID NO:3674); miR-365-2 (SEQ ID NO:3675); miR-367 (SEQ ID NO:3676); miR-369 (SEQ ID NO:3677); miR-370 (SEQ ID NO:3678); miR-374b (SEQ ID NO:3679); miR-374c (SEQ ID NO:3680); miR-375 (SEQ ID NO:3681); miR-376a (SEQ ID NO:3682); miR-376b (SEQ ID NO:3683); miR-376c (SEQ ID NO:3684); miR-377 (SEQ ID NO:3685); miR-378a (SEQ ID NO:3686); miR-378b (SEQ ID NO:3687); miR-378c (SEQ ID NO:3688); miR-378d (SEQ ID NO:3689); miR-379 (SEQ ID NO:3690); miR-380 (SEQ ID NO:3691); miR-381 (SEQ ID NO:3692); miR-382 (SEQ ID NO:3693); miR-383 (SEQ ID NO:3694); miR-384 (SEQ ID NO:3695); miR-409 (SEQ ID NO:3696); miR-410 (SEQ ID NO:3697); miR-411 (SEQ ID NO:3698); miR-412 (SEQ ID NO:3699); miR-421 (SEQ ID NO:3700); miR-423 (SEQ ID NO:3701); miR-425 (SEQ ID NO:3702); miR-429 (SEQ ID NO:3703); miR-431 (SEQ ID NO:3704); miR-432 (SEQ ID NO:3705); miR-433 (SEQ ID NO:3706); miR-434 (SEQ ID NO:3707); miR-448 (SEQ ID NO:3708); miR-449a (SEQ ID NO:3709); miR-449b (SEQ ID NO:3710); miR-449c (SEQ ID NO:3711); miR-450a-1 (SEQ ID NO:3712); miR-450a-2 (SEQ ID NO:3713); miR-450b (SEQ ID NO:3714); miR-451a (SEQ ID NO:3715); miR-451b (SEQ ID NO:3716); miR-452 (SEQ ID NO:3717); miR-453 (SEQ ID NO:3718); miR-455 (SEQ ID NO:3719); miR-463 (SEQ ID NO:3720); miR-465a (SEQ ID NO:3721); miR-465b-1 (SEQ ID NO:3722); miR-465b-2 (SEQ ID NO:3723); miR-465c-1 (SEQ ID NO:3724); miR-465c-2 (SEQ ID NO:3725); miR-465d (SEQ ID NO:3726); miR-466a (SEQ ID NO:3727); miR-466b-1 (SEQ ID NO:3728); miR-466b-2 (SEQ ID NO:3729); miR-466b-3 (SEQ ID NO:3730); miR-466b-4 (SEQ ID NO:3731); miR-466b-5 (SEQ ID NO:3732); miR-466b-6 (SEQ ID NO:3733); miR-466b-7 (SEQ ID NO:3734); miR-466b-8 (SEQ ID NO:3735); miR-466c-1 (SEQ ID NO:3736); miR-466c-2 (SEQ ID NO:3737); miR-466d (SEQ ID NO:3738); miR-466e (SEQ ID NO:3739); miR-466f-1 (SEQ ID NO:3740); miR-466f-2 (SEQ ID NO:3741); miR-466f-3 (SEQ ID NO:3742); miR-466f-4 (SEQ ID NO:3743); miR-466g (SEQ ID NO:3744); miR-466h (SEQ ID NO:3745); miR-466i (SEQ ID NO:3746); miR-466j (SEQ ID NO:3747); miR-466k (SEQ ID NO:3748); miR-466l (SEQ ID NO:3749); miR-466m (SEQ ID NO:3750); miR-466n (SEQ ID NO:3751); miR-466o (SEQ ID NO:3752); miR-466p (SEQ ID NO:3753); miR-466q (SEQ ID NO:3754); miR-467a-1 (SEQ ID NO:3755); miR-467a-10 (SEQ ID NO:3756); miR-467a-2 (SEQ ID NO:3757); miR-467a-3 (SEQ ID NO:3758); miR-467a-4 (SEQ ID NO:3759); miR-467a-5 (SEQ ID NO:3760); miR-467a-6 (SEQ ID NO:3761); miR-467a-7 (SEQ ID NO:3762); miR-467a-8 (SEQ ID NO:3763); miR-467a-9 (SEQ ID NO:3764); miR-467b (SEQ ID NO:3765); miR-467c (SEQ ID NO:3766); miR-467d (SEQ ID NO:3767); miR-467e (SEQ ID NO:3768); miR-467f (SEQ ID NO:3769); miR-467g (SEQ ID NO:3770); miR-467h (SEQ ID NO:3771); miR-468 (SEQ ID NO:3772); miR-470 (SEQ ID NO:3773); miR-471 (SEQ ID NO:3774); miR-483 (SEQ ID NO:3775); miR-484 (SEQ ID NO:3776); miR-485 (SEQ ID NO:3777); miR-486 (SEQ ID NO:3778); miR-487b (SEQ ID NO:3779); miR-488 (SEQ ID NO:3780); miR-489 (SEQ ID NO:3781); miR-490 (SEQ ID NO:3782); miR-491 (SEQ ID NO:3783); miR-493 (SEQ ID NO:3784); miR-494 (SEQ ID NO:3785); miR-495 (SEQ ID NO:3786); miR-496a (SEQ ID NO:3787); miR-496b (SEQ ID NO:3788); miR-497 (SEQ ID NO:3789); miR-497b (SEQ ID NO:3790); miR-499 (SEQ ID NO:3791); miR-500 (SEQ ID NO:3792); miR-501 (SEQ ID NO:3793); miR-503 (SEQ ID NO:3794); miR-504 (SEQ ID NO:3795); miR-505 (SEQ ID NO:3796); miR-509 (SEQ ID NO:3797); miR-511 (SEQ ID NO:3798); miR-532 (SEQ ID NO:3799); miR-539 (SEQ ID NO:3800); miR-540 (SEQ ID NO:3801); miR-541 (SEQ ID NO:3802); miR-542 (SEQ ID NO:3803); miR-543 (SEQ ID NO:3804); miR-544 (SEQ ID NO:3805); miR-546 (SEQ ID NO:3806); miR-547 (SEQ ID NO:3807); miR-551b (SEQ ID NO:3808); miR-568 (SEQ ID NO:3809); miR-574 (SEQ ID NO:3810); miR-582 (SEQ ID NO:3811); miR-590 (SEQ ID NO:3812); miR-592 (SEQ ID NO:3813); miR-598 (SEQ ID NO:3814); miR-599 (SEQ ID NO:3815); miR-615 (SEQ ID NO:3816); miR-652 (SEQ ID NO:3817); miR-653 (SEQ ID NO:3818); miR-654 (SEQ ID NO:3819); miR-664 (SEQ ID NO:3820); miR-665 (SEQ ID NO:3821); miR-666 (SEQ ID NO:3822); miR-667 (SEQ ID NO:3823); miR-668 (SEQ ID NO:3824); miR-669a-1 (SEQ ID NO:3825); miR-669a-10 (SEQ ID NO:3826); miR-669a-11 (SEQ ID NO:3827); miR-669a-12 (SEQ ID NO:3828); miR-669a-2 (SEQ ID NO:3829); miR-669a-3 (SEQ ID NO:3830); miR-669a-4 (SEQ ID NO:3831); miR-669a-5 (SEQ ID NO:3832); miR-669a-6 (SEQ ID NO:3833); miR-669a-7 (SEQ ID NO:3834); miR-669a-8 (SEQ ID NO:3835); miR-669a-9 (SEQ ID NO:3836); miR-669b (SEQ ID NO:3837); miR-669c (SEQ ID NO:3838); miR-669d (SEQ ID NO:3839); miR-669d-2 (SEQ ID NO:3840); miR-669e (SEQ ID NO:3841); miR-669f (SEQ ID NO:3842); miR-669g (SEQ ID NO:3843); miR-669h (SEQ ID NO:3844); miR-669i (SEQ ID NO:3845); miR-669j (SEQ ID NO:3846); miR-669k (SEQ ID NO:3847); miR-669l (SEQ ID NO:3848); miR-669m-1 (SEQ ID NO:3849); miR-669m-2 (SEQ ID NO:3850); miR-669n (SEQ ID NO:3851); miR-669o (SEQ ID NO:3852); miR-669p-1 (SEQ ID NO:3853); miR-669p-2 (SEQ ID NO:3854); miR-670 (SEQ ID NO:3855); miR-671 (SEQ ID NO:3856); miR-672 (SEQ ID NO:3857); miR-673 (SEQ ID NO:3858); miR-674 (SEQ ID NO:3859); miR-675 (SEQ ID NO:3860); miR-676 (SEQ ID NO:3861); miR-677 (SEQ ID NO:3862); miR-678 (SEQ ID NO:3863); miR-679 (SEQ ID NO:3864); miR-680-1 (SEQ ID NO:3865); miR-680-2 (SEQ ID NO:3866); miR-680-3 (SEQ ID NO:3867); miR-681 (SEQ ID NO:3868); miR-682 (SEQ ID NO:3869); miR-683-1 (SEQ ID NO:3870); miR-683-2 (SEQ ID NO:3871); miR-684-1 (SEQ ID NO:3872); miR-684-2 (SEQ ID NO:3873); miR-686 (SEQ ID NO:3874); miR-687 (SEQ ID NO:3875); miR-688 (SEQ ID NO:3876); miR-690 (SEQ ID NO:3877); miR-691 (SEQ ID NO:3878); miR-692-1 (SEQ ID NO:3879); miR-692-2 (SEQ ID NO:3880); miR-692-3 (SEQ ID NO:3881); miR-693 (SEQ ID NO:3882); miR-694 (SEQ ID NO:3883); miR-695 (SEQ ID NO:3884); miR-696 (SEQ ID NO:3885); miR-697 (SEQ ID NO:3886); miR-698 (SEQ ID NO:3887); miR-700 (SEQ ID NO:3888); miR-701 (SEQ ID NO:3889); miR-702 (SEQ ID NO:3890); miR-703 (SEQ ID NO:3891); miR-704 (SEQ ID NO:3892); miR-705 (SEQ ID NO:3893); miR-706 (SEQ ID NO:3894); miR-707 (SEQ ID NO:3895); miR-708 (SEQ ID NO:3896); miR-709 (SEQ ID NO:3897); miR-710 (SEQ ID NO:3898); miR-711 (SEQ ID NO:3899); miR-712 (SEQ ID NO:3900); miR-713 (SEQ ID NO:3901); miR-714 (SEQ ID NO:3902); miR-717 (SEQ ID NO:3903); miR-718 (SEQ ID NO:3904); miR-719 (SEQ ID NO:3905); miR-721 (SEQ ID NO:3906); miR-741 (SEQ ID NO:3907); miR-742 (SEQ ID NO:3908); miR-743a (SEQ ID NO:3909); miR-743b (SEQ ID NO:3910); miR-744 (SEQ ID NO:3911); miR-758 (SEQ ID NO:3912); miR-759 (SEQ ID NO:3913); miR-760 (SEQ ID NO:3914); miR-761 (SEQ ID NO:3915); miR-762 (SEQ ID NO:3916); miR-763 (SEQ ID NO:3917); miR-764 (SEQ ID NO:3918); miR-767 (SEQ ID NO:3919); miR-770 (SEQ ID NO:3920); miR-802 (SEQ ID NO:3921); miR-804 (SEQ ID NO:3922); miR-871 (SEQ ID NO:3923); miR-872 (SEQ ID NO:3924); miR-873a (SEQ ID NO:3925); miR-873b (SEQ ID NO:3926); miR-874 (SEQ ID NO:3927); miR-875 (SEQ ID NO:3928); miR-876 (SEQ ID NO:3929); miR-877 (SEQ ID NO:3930); miR-878 (SEQ ID NO:3931); miR-879 (SEQ ID NO:3932); miR-880 (SEQ ID NO:3933); miR-881 (SEQ ID NO:3934); miR-882 (SEQ ID NO:3935); miR-883a (SEQ ID NO:3936); miR-883b (SEQ ID NO:3937); miR-1187 (SEQ ID NO:3938); miR-1188 (SEQ ID NO:3939); miR-1190 (SEQ ID NO:3940); miR-1191 (SEQ ID NO:3941); miR-1191b (SEQ ID NO:3942); miR-1192 (SEQ ID NO:3943); miR-1193 (SEQ ID NO:3944); miR-1194 (SEQ ID NO:3945); miR-1195 (SEQ ID NO:3946); miR-1197 (SEQ ID NO:3947); miR-1198 (SEQ ID NO:3948); miR-1199 (SEQ ID NO:3949); miR-1224 (SEQ ID NO:3950); miR-1231 (SEQ ID NO:3951); miR-1247 (SEQ ID NO:3952); miR-1249 (SEQ ID NO:3953); miR-1251 (SEQ ID NO:3954); miR-1258 (SEQ ID NO:3955); miR-1264 (SEQ ID NO:3956); miR-1291 (SEQ ID NO:3957); miR-1298 (SEQ ID NO:3958); miR-1306 (SEQ ID NO:3959); miR-1668 (SEQ ID NO:3960); miR-1839 (SEQ ID NO:3961); miR-1843a (SEQ ID NO:3962); miR-1843b (SEQ ID NO:3963); miR-1892 (SEQ ID NO:3964); miR-1893 (SEQ ID NO:3965); miR-1894 (SEQ ID NO:3966); miR-1895 (SEQ ID NO:3967); miR-1896 (SEQ ID NO:3968); miR-1897 (SEQ ID NO:3969); miR-1898 (SEQ ID NO:3970); miR-1899 (SEQ ID NO:3971); miR-1900 (SEQ ID NO:3972); miR-1901 (SEQ ID NO:3973); miR-1902 (SEQ ID NO:3974); miR-1903 (SEQ ID NO:3975); miR-1904 (SEQ ID NO:3976); miR-1905 (SEQ ID NO:3977); miR-1906-1 (SEQ ID NO:3978); miR-1906-2 (SEQ ID NO:3979); miR-1907 (SEQ ID NO:3980); miR-1912 (SEQ ID NO:3981); miR-1927 (SEQ ID NO:3982); miR-1928 (SEQ ID NO:3983); miR-1929 (SEQ ID NO:3984); miR-1930 (SEQ ID NO:3985); miR-1931 (SEQ ID NO:3986); miR-1932 (SEQ ID NO:3987); miR-1933 (SEQ ID NO:3988); miR-1934 (SEQ ID NO:3989); miR-1936 (SEQ ID NO:3990); miR-1938 (SEQ ID NO:3991); miR-1940 (SEQ ID NO:3992); miR-1941 (SEQ ID NO:3993); miR-1942 (SEQ ID NO:3994); miR-1943 (SEQ ID NO:3995); miR-1945 (SEQ ID NO:3996); miR-1946a (SEQ ID NO:3997); miR-1946b (SEQ ID NO:3998); miR-1947 (SEQ ID NO:3999); miR-1948 (SEQ ID NO:4000); miR-1949 (SEQ ID NO:4001); miR-1950 (SEQ ID NO:4002); miR-1951 (SEQ ID NO:4003); miR-1952 (SEQ ID NO:4004); miR-1953 (SEQ ID NO:4005); miR-1954 (SEQ ID NO:4006); miR-1955 (SEQ ID NO:4007); miR-1956 (SEQ ID NO:4008); miR-1957a (SEQ ID NO:4009); miR-1957b (SEQ ID NO:4010); miR-1958 (SEQ ID NO:4011); miR-1960 (SEQ ID NO:4012); miR-1961 (SEQ ID NO:4013); miR-1962 (SEQ ID NO:4014); miR-1963 (SEQ ID NO:4015); miR-1964 (SEQ ID NO:4016); miR-1966 (SEQ ID NO:4017); miR-1967 (SEQ ID NO:4018); miR-1968 (SEQ ID NO:4019); miR-1969 (SEQ ID NO:4020); miR-1970 (SEQ ID NO:4021); miR-1971 (SEQ ID NO:4022); miR-1981 (SEQ ID NO:4023); miR-1982 (SEQ ID NO:4024); miR-1983 (SEQ ID NO:4025); miR-2136 (SEQ ID NO:4026); miR-2137 (SEQ ID NO:4027); miR-2139 (SEQ ID NO:4028); miR-2183 (SEQ ID NO:4029); miR-2861 (SEQ ID NO:4030); miR-3057 (SEQ ID NO:4031); miR-3058 (SEQ ID NO:4032); miR-3059 (SEQ ID NO:4033); miR-3060 (SEQ ID NO:4034); miR-3061 (SEQ ID NO:4035); miR-3062 (SEQ ID NO:4036); miR-3063 (SEQ ID NO:4037); miR-3064 (SEQ ID NO:4038); miR-3065 (SEQ ID NO:4039); miR-3066 (SEQ ID NO:4040); miR-3067 (SEQ ID NO:4041); miR-3068 (SEQ ID NO:4042); miR-3069 (SEQ ID NO:4043); miR-3070a (SEQ ID NO:4044); miR-3070b (SEQ ID NO:4045); miR-3071 (SEQ ID NO:4046); miR-3072 (SEQ ID NO:4047); miR-3073a (SEQ ID NO:4048); miR-3073b (SEQ ID NO:4049); miR-3074-1 (SEQ ID NO:4050); miR-3074-2 (SEQ ID NO:4051); miR-3075 (SEQ ID NO:4052); miR-3076 (SEQ ID NO:4053); miR-3077 (SEQ ID NO:4054); miR-3078 (SEQ ID NO:4055); miR-3079 (SEQ ID NO:4056); miR-3080 (SEQ ID NO:4057); miR-3081 (SEQ ID NO:4058); miR-3082 (SEQ ID NO:4059); miR-3083 (SEQ ID NO:4060); miR-3084-1 (SEQ ID NO:4061); miR-3084-2 (SEQ ID NO:4062); miR-3085 (SEQ ID NO:4063); miR-3086 (SEQ ID NO:4064); miR-3087 (SEQ ID NO:4065); miR-3088 (SEQ ID NO:4066); miR-3089 (SEQ ID NO:4067); miR-3090 (SEQ ID NO:4068); miR-3091 (SEQ ID NO:4069); miR-3092 (SEQ ID NO:4070); miR-3093 (SEQ ID NO:4071); miR-3094 (SEQ ID NO:4072); miR-3095 (SEQ ID NO:4073); miR-3097 (SEQ ID NO:4074); miR-3098 (SEQ ID NO:4075); miR-3099 (SEQ ID NO:4076); miR-3100 (SEQ ID NO:4077); miR-3101 (SEQ ID NO:4078); miR-3102 (SEQ ID NO:4079); miR-3103 (SEQ ID NO:4080); miR-3104 (SEQ ID NO:4081); miR-3105 (SEQ ID NO:4082); miR-3106 (SEQ ID NO:4083); miR-3107 (SEQ ID NO:4084); miR-3108 (SEQ ID NO:4085); miR-3109 (SEQ ID NO:4086); miR-3110 (SEQ ID NO:4087); miR-3112 (SEQ ID NO:4088); miR-3113 (SEQ ID NO:4089); miR-3470a (SEQ ID NO:4090); miR-3470b (SEQ ID NO:4091); miR-3471-1 (SEQ ID NO:4092); miR-3471-2 (SEQ ID NO:4093); miR-3472 (SEQ ID NO:4094); miR-3473a (SEQ ID NO:4095); miR-3473b (SEQ ID NO:4096); miR-3473c (SEQ ID NO:4097); miR-3473d (SEQ ID NO:4098); miR-3473e (SEQ ID NO:4099); miR-3473f (SEQ ID NO:4100); miR-3473g (SEQ ID NO:4101); miR-3474 (SEQ ID NO:4102); miR-3475 (SEQ ID NO:4103); miR-3535 (SEQ ID NO:4104); miR-3544 (SEQ ID NO:4105); miR-3547 (SEQ ID NO:4106); miR-3569 (SEQ ID NO:4107); miR-3572 (SEQ ID NO:4108); miR-3620 (SEQ ID NO:4109); miR-3960 (SEQ ID NO:4110); miR-3961 (SEQ ID NO:4111); miR-3962 (SEQ ID NO:4112); miR-3963 (SEQ ID NO:4113); miR-3964 (SEQ ID NO:4114); miR-3965 (SEQ ID NO:4115); miR-3966 (SEQ ID NO:4116); miR-3967 (SEQ ID NO:4117); miR-3968 (SEQ ID NO:4118); miR-3969 (SEQ ID NO:4119); miR-3970 (SEQ ID NO:4120); miR-3971 (SEQ ID NO:4121); miR-5046 (SEQ ID NO:4122); miR-5098 (SEQ ID NO:4123); miR-5099 (SEQ ID NO:4124); miR-5100 (SEQ ID NO:4125); miR-5101 (SEQ ID NO:4126); miR-5103 (SEQ ID NO:4127); miR-5104 (SEQ ID NO:4128); miR-5106 (SEQ ID NO:4129); miR-5107 (SEQ ID NO:4130); miR-5108 (SEQ ID NO:4131); miR-5110 (SEQ ID NO:4132); miR-5112 (SEQ ID NO:4133); miR-5113 (SEQ ID NO:4134); miR-5114 (SEQ ID NO:4135); miR-5116 (SEQ ID NO:4136); miR-5118 (SEQ ID NO:4137); miR-5119 (SEQ ID NO:4138); miR-5120 (SEQ ID NO:4139); miR-5121 (SEQ ID NO:4140); miR-5122 (SEQ ID NO:4141); miR-5123 (SEQ ID NO:4142); miR-5124a (SEQ ID NO:4143); miR-5124b (SEQ ID NO:4144); miR-5125 (SEQ ID NO:4145); miR-5126 (SEQ ID NO:4146); miR-5127 (SEQ ID NO:4147); miR-5128 (SEQ ID NO:4148); miR-5129 (SEQ ID NO:4149); miR-5130 (SEQ ID NO:4150); miR-5131 (SEQ ID NO:4151); miR-5132 (SEQ ID NO:4152); miR-5133 (SEQ ID NO:4153); miR-5134 (SEQ ID NO:4154); miR-5135 (SEQ ID NO:4155); miR-5136 (SEQ ID NO:4156); miR-5615-1 (SEQ ID NO:4157); miR-5615-2 (SEQ ID NO:4158); miR-5616 (SEQ ID NO:4159); miR-5617 (SEQ ID NO:4160); miR-5618 (SEQ ID NO:4161); miR-5619 (SEQ ID NO:4162); miR-5620 (SEQ ID NO:4163); miR-5621 (SEQ ID NO:4164); miR-5622 (SEQ ID NO:4165); miR-5623 (SEQ ID NO:4166); miR-5624 (SEQ ID NO:4167); miR-5625 (SEQ ID NO:4168); miR-5626 (SEQ ID NO:4169); miR-5627 (SEQ ID NO:4170); miR-5709 (SEQ ID NO:4171); miR-5710 (SEQ ID NO:4172); miR-6236 (SEQ ID NO:4173); miR-6237 (SEQ ID NO:4174); miR-6238 (SEQ ID NO:4175); miR-6239 (SEQ ID NO:4176); miR-6240 (SEQ ID NO:4177); miR-6241 (SEQ ID NO:4178); miR-6244 (SEQ ID NO:4179); miR-6335 (SEQ ID NO:4180); miR-6336 (SEQ ID NO:4181); miR-6337 (SEQ ID NO:4182); miR-6338 (SEQ ID NO:4183); miR-6339 (SEQ ID NO:4184); miR-6340 (SEQ ID NO:4185); miR-6341 (SEQ ID NO:4186); miR-6342 (SEQ ID NO:4187); miR-6343 (SEQ ID NO:4188); miR-6344 (SEQ ID NO:4189); miR-6345 (SEQ ID NO:4190); miR-6346 (SEQ ID NO:4191); miR-6347 (SEQ ID NO:4192); miR-6348 (SEQ ID NO:4193); miR-6349 (SEQ ID NO:4194); miR-6350 (SEQ ID NO:4195); miR-6351 (SEQ ID NO:4196); miR-6352 (SEQ ID NO:4197); miR-6353 (SEQ ID NO:4198); miR-6354 (SEQ ID NO:4199); miR-6355 (SEQ ID NO:4200); miR-6356 (SEQ ID NO:4201); miR-6357 (SEQ ID NO:4202); miR-6358 (SEQ ID NO:4203); miR-6359 (SEQ ID NO:4204); miR-6360 (SEQ ID NO:4205); miR-6361 (SEQ ID NO:4206); miR-6362 (SEQ ID NO:4207); miR-6363 (SEQ ID NO:4208); miR-6364 (SEQ ID NO:4209); miR-6365 (SEQ ID NO:4210); miR-6366 (SEQ ID NO:4211); miR-6367 (SEQ ID NO:4212); miR-6368 (SEQ ID NO:4213); miR-6369 (SEQ ID NO:4214); miR-6370 (SEQ ID NO:4215); miR-6371 (SEQ ID NO:4216); miR-6372 (SEQ ID NO:4217); miR-6373 (SEQ ID NO:4218); miR-6374 (SEQ ID NO:4219); miR-6375 (SEQ ID NO:4220); miR-6376 (SEQ ID NO:4221); miR-6377 (SEQ ID NO:4222); miR-6378 (SEQ ID NO:4223); miR-6379 (SEQ ID NO:4224); miR-6380 (SEQ ID NO:4225); miR-6381 (SEQ ID NO:4226); miR-6382 (SEQ ID NO:4227); miR-6383 (SEQ ID NO:4228); miR-6384 (SEQ ID NO:4229); miR-6385 (SEQ ID NO:4230); miR-6386 (SEQ ID NO:4231); miR-6387 (SEQ ID NO:4232); miR-6388 (SEQ ID NO:4233); miR-6389 (SEQ ID NO:4234); miR-6390 (SEQ ID NO:4235); miR-6391 (SEQ ID NO:4236); miR-6392 (SEQ ID NO:4237); miR-6393 (SEQ ID NO:4238); miR-6394 (SEQ ID NO:4239); miR-6395 (SEQ ID NO:4240); miR-6396 (SEQ ID NO:4241); miR-6397 (SEQ ID NO:4242); miR-6398 (SEQ ID NO:4243); miR-6399 (SEQ ID NO:4244); miR-6400 (SEQ ID NO:4245); miR-6401 (SEQ ID NO:4246); miR-6402 (SEQ ID NO:4247); miR-6403 (SEQ ID NO:4248); miR-6404 (SEQ ID NO:4249); miR-6405 (SEQ ID NO:4250); miR-6406 (SEQ ID NO:4251); miR-6407 (SEQ ID NO:4252); miR-6408 (SEQ ID NO:4253); miR-6409 (SEQ ID NO:4254); miR-6410 (SEQ ID NO:4255); miR-6411 (SEQ ID NO:4256); miR-6412 (SEQ ID NO:4257); miR-6413 (SEQ ID NO:4258); miR-6414 (SEQ ID NO:4259); miR-6415 (SEQ ID NO:4260); miR-6416 (SEQ ID NO:4261); miR-6417 (SEQ ID NO:4262); miR-6418 (SEQ ID NO:4263); miR-6419 (SEQ ID NO:4264); miR-6420 (SEQ ID NO:4265); miR-6481 (SEQ ID NO:4266); miR-6516 (SEQ ID NO:4267); miR-6537 (SEQ ID NO:4268); miR-6538 (SEQ ID NO:4269); miR-6539 (SEQ ID NO:4270); miR-6540 (SEQ ID NO:4271); miR-6541 (SEQ ID NO:4272); miR-6546 (SEQ ID NO:4273); miR-6715 (SEQ ID NO:4274); miR-6769b (SEQ ID NO:4275); miR-6896 (SEQ ID NO:4276); miR-6897 (SEQ ID NO:4277); miR-6898 (SEQ ID NO:4278); miR-6899 (SEQ ID NO:4279); miR-6900 (SEQ ID NO:4280); miR-6901 (SEQ ID NO:4281); miR-6902 (SEQ ID NO:4282); miR-6903 (SEQ ID NO:4283); miR-6904 (SEQ ID NO:4284); miR-6905 (SEQ ID NO:4285); miR-6906 (SEQ ID NO:4286); miR-6907 (SEQ ID NO:4287); miR-6908 (SEQ ID NO:4288); miR-6909 (SEQ ID NO:4289); miR-6910 (SEQ ID NO:4290); miR-6911 (SEQ ID NO:4291); miR-6912 (SEQ ID NO:4292); miR-6913 (SEQ ID NO:4293); miR-6914 (SEQ ID NO:4294); miR-6915 (SEQ ID NO:4295); miR-6916 (SEQ ID NO:4296); miR-6917 (SEQ ID NO:4297); miR-6918 (SEQ ID NO:4298); miR-6919 (SEQ ID NO:4299); miR-6920 (SEQ ID NO:4300); miR-6921 (SEQ ID NO:4301); miR-6922 (SEQ ID NO:4302); miR-6923 (SEQ ID NO:4303); miR-6924 (SEQ ID NO:4304); miR-6925 (SEQ ID NO:4305); miR-6926 (SEQ ID NO:4306); miR-6927 (SEQ ID NO:4307); miR-6928 (SEQ ID NO:4308); miR-6929 (SEQ ID NO:4309); miR-6930 (SEQ ID NO:4310); miR-6931 (SEQ ID NO:4311); miR-6932 (SEQ ID NO:4312); miR-6933 (SEQ ID NO:4313); miR-6934 (SEQ ID NO:4314); miR-6935 (SEQ ID NO:4315); miR-6936 (SEQ ID NO:4316); miR-6937 (SEQ ID NO:4317); miR-6938 (SEQ ID NO:4318); miR-6939 (SEQ ID NO:4319); miR-6940 (SEQ ID NO:4320); miR-6941 (SEQ ID NO:4321); miR-6942 (SEQ ID NO:4322); miR-6943 (SEQ ID NO:4323); miR-6944 (SEQ ID NO:4324); miR-6945 (SEQ ID NO:4325); miR-6946 (SEQ ID NO:4326); miR-6947 (SEQ ID NO:4327); miR-6948 (SEQ ID NO:4328); miR-6949 (SEQ ID NO:4329); miR-6950 (SEQ ID NO:4330); miR-6951 (SEQ ID NO:4331); miR-6952 (SEQ ID NO:4332); miR-6953 (SEQ ID NO:4333); miR-6954 (SEQ ID NO:4334); miR-6955 (SEQ ID NO:4335); miR-6956 (SEQ ID NO:4336); miR-6957 (SEQ ID NO:4337); miR-6958 (SEQ ID NO:4338); miR-6959 (SEQ ID NO:4339); miR-6960 (SEQ ID NO:4340); miR-6961 (SEQ ID NO:4341); miR-6962 (SEQ ID NO:4342); miR-6963 (SEQ ID NO:4343); miR-6964 (SEQ ID NO:4344); miR-6965 (SEQ ID NO:4345); miR-6966 (SEQ ID NO:4346); miR-6967 (SEQ ID NO:4347); miR-6968 (SEQ ID NO:4348); miR-6969 (SEQ ID NO:4349); miR-6970 (SEQ ID NO:4350); miR-6971 (SEQ ID NO:4351); miR-6972 (SEQ ID NO:4352); miR-6973a (SEQ ID NO:4353); miR-6973b (SEQ ID NO:4354); miR-6974 (SEQ ID NO:4355); miR-6975 (SEQ ID NO:4356); miR-6976 (SEQ ID NO:4357); miR-6977 (SEQ ID NO:4358); miR-6978 (SEQ ID NO:4359); miR-6979 (SEQ ID NO:4360); miR-6980 (SEQ ID NO:4361); miR-6981 (SEQ ID NO:4362); miR-6982 (SEQ ID NO:4363); miR-6983 (SEQ ID NO:4364); miR-6984 (SEQ ID NO:4365); miR-6985 (SEQ ID NO:4366); miR-6986 (SEQ ID NO:4367); miR-6987 (SEQ ID NO:4368); miR-6988 (SEQ ID NO:4369); miR-6989 (SEQ ID NO:4370); miR-6990 (SEQ ID NO:4371); miR-6991 (SEQ ID NO:4372); miR-6992 (SEQ ID NO:4373); miR-6993 (SEQ ID NO:4374); miR-6994 (SEQ ID NO:4375); miR-6995 (SEQ ID NO:4376); miR-6996 (SEQ ID NO:4377); miR-6997 (SEQ ID NO:4378); miR-6998 (SEQ ID NO:4379); miR-6999 (SEQ ID NO:4380); miR-7000 (SEQ ID NO:4381); miR-7001 (SEQ ID NO:4382); miR-7002 (SEQ ID NO:4383); miR-7003 (SEQ ID NO:4384); miR-7004 (SEQ ID NO:4385); miR-7005 (SEQ ID NO:4386); miR-7006 (SEQ ID NO:4387); miR-7007 (SEQ ID NO:4388); miR-7008 (SEQ ID NO:4389); miR-7009 (SEQ ID NO:4390); miR-7010 (SEQ ID NO:4391); miR-7011 (SEQ ID NO:4392); miR-7012 (SEQ ID NO:4393); miR-7013 (SEQ ID NO:4394); miR-7014 (SEQ ID NO:4395); miR-7015 (SEQ ID NO:4396); miR-7016 (SEQ ID NO:4397); miR-7017 (SEQ ID NO:4398); miR-7018 (SEQ ID NO:4399); miR-7019 (SEQ ID NO:4400); miR-7020 (SEQ ID NO:4401); miR-7021 (SEQ ID NO:4402); miR-7022 (SEQ ID NO:4403); miR-7023 (SEQ ID NO:4404); miR-7024 (SEQ ID NO:4405); miR-7025 (SEQ ID NO:4406); miR-7026 (SEQ ID NO:4407); miR-7027 (SEQ ID NO:4408); miR-7028 (SEQ ID NO:4409); miR-7029 (SEQ ID NO:4410); miR-7030 (SEQ ID NO:4411); miR-7031 (SEQ ID NO:4412); miR-7032 (SEQ ID NO:4413); miR-7033 (SEQ ID NO:4414); miR-7034 (SEQ ID NO:4415); miR-7035 (SEQ ID NO:4416); miR-7036 (SEQ ID NO:4417); miR-7036b (SEQ ID NO:4418); miR-7037 (SEQ ID NO:4419); miR-7038 (SEQ ID NO:4420); miR-7039 (SEQ ID NO:4421); miR-7040 (SEQ ID NO:4422); miR-7041 (SEQ ID NO:4423); miR-7042 (SEQ ID NO:4424); miR-7043 (SEQ ID NO:4425); miR-7044 (SEQ ID NO:4426); miR-7045 (SEQ ID NO:4427); miR-7046 (SEQ ID NO:4428); miR-7047 (SEQ ID NO:4429); miR-7048 (SEQ ID NO:4430); miR-7049 (SEQ ID NO:4431); miR-7050 (SEQ ID NO:4432); miR-7051 (SEQ ID NO:4433); miR-7052 (SEQ ID NO:4434); miR-7053 (SEQ ID NO:4435); miR-7054 (SEQ ID NO:4436); miR-7055 (SEQ ID NO:4437); miR-7056 (SEQ ID NO:4438); miR-7057 (SEQ ID NO:4439); miR-7058 (SEQ ID NO:4440); miR-7059 (SEQ ID NO:4441); miR-7060 (SEQ ID NO:4442); miR-7061 (SEQ ID NO:4443); miR-7062 (SEQ ID NO:4444); miR-7063 (SEQ ID NO:4445); miR-7064 (SEQ ID NO:4446); miR-7065 (SEQ ID NO:4447); miR-7066 (SEQ ID NO:4448); miR-7067 (SEQ ID NO:4449); miR-7068 (SEQ ID NO:4450); miR-7069 (SEQ ID NO:4451); miR-7070 (SEQ ID NO:4452); miR-7071 (SEQ ID NO:4453); miR-7072 (SEQ ID NO:4454); miR-7073 (SEQ ID NO:4455); miR-7074 (SEQ ID NO:4456); miR-7075 (SEQ ID NO:4457); miR-7076 (SEQ ID NO:4458); miR-7077 (SEQ ID NO:4459); miR-7078 (SEQ ID NO:4460); miR-7079 (SEQ ID NO:4461); miR-7080 (SEQ ID NO:4462); miR-7081 (SEQ ID NO:4463); miR-7082 (SEQ ID NO:4464); miR-7083 (SEQ ID NO:4465); miR-7084 (SEQ ID NO:4466); miR-7085 (SEQ ID NO:4467); miR-7086 (SEQ ID NO:4468); miR-7087 (SEQ ID NO:4469); miR-7088 (SEQ ID NO:4470); miR-7089 (SEQ ID NO:4471); miR-7090 (SEQ ID NO:4472); miR-7091 (SEQ ID NO:4473); miR-7092 (SEQ ID NO:4474); miR-7093 (SEQ ID NO:4475); miR-7094-1 (SEQ ID NO:4476); miR-7094-2 (SEQ ID NO:4477); miR-7115 (SEQ ID NO:4478); miR-7116 (SEQ ID NO:4479); miR-7117 (SEQ ID NO:4480); miR-7118 (SEQ ID NO:4481); miR-7119 (SEQ ID NO:4482); miR-7210 (SEQ ID NO:4483); miR-7211 (SEQ ID NO:4484); miR-7212 (SEQ ID NO:4485); miR-7213 (SEQ ID NO:4486); miR-7214 (SEQ ID NO:4487); miR-7215 (SEQ ID NO:4488); miR-7216 (SEQ ID NO:4489); miR-7217 (SEQ ID NO:4490); miR-7218 (SEQ ID NO:4491); miR-7219 (SEQ ID NO:4492); miR-7220 (SEQ ID NO:4493); miR-7221 (SEQ ID NO:4494); miR-7222 (SEQ ID NO:4495); miR-7223 (SEQ ID NO:4496); miR-7224 (SEQ ID NO:4497); miR-7225 (SEQ ID NO:4498); miR-7226 (SEQ ID NO:4499); miR-7227 (SEQ ID NO:4500); miR-7228 (SEQ ID NO:4501); miR-7229 (SEQ ID NO:4502); miR-7230 (SEQ ID NO:4503); miR-7231 (SEQ ID NO:4504); miR-7232 (SEQ ID NO:4505); miR-7233 (SEQ ID NO:4506); miR-7234 (SEQ ID NO:4507); miR-7235 (SEQ ID NO:4508); miR-7236 (SEQ ID NO:4509); miR-7237 (SEQ ID NO:4510); miR-7238 (SEQ ID NO:4511); miR-7239 (SEQ ID NO:4512); miR-7240 (SEQ ID NO:4513); miR-7241 (SEQ ID NO:4514); miR-7242 (SEQ ID NO:4515); miR-7243 (SEQ ID NO:4516); miR-7578 (SEQ ID NO:4517); miR-7646 (SEQ ID NO:4518); miR-7647 (SEQ ID NO:4519); miR-7648 (SEQ ID NO:4520); miR-7649 (SEQ ID NO:4521); miR-7650 (SEQ ID NO:4522); miR-7651 (SEQ ID NO:4523); miR-7652 (SEQ ID NO:4524); miR-7653 (SEQ ID NO:4525); miR-7654 (SEQ ID NO:4526); miR-7655 (SEQ ID NO:4527); miR-7656 (SEQ ID NO:4528); miR-7657 (SEQ ID NO:4529); miR-7658 (SEQ ID NO:4530); miR-7659 (SEQ ID NO:4531); miR-7660 (SEQ ID NO:4532); miR-7661 (SEQ ID NO:4533); miR-7662 (SEQ ID NO:4534); miR-7663 (SEQ ID NO:4535); miR-7664 (SEQ ID NO:4536); miR-7665 (SEQ ID NO:4537); miR-7666 (SEQ ID NO:4538); miR-7667 (SEQ ID NO:4539); miR-7668 (SEQ ID NO:4540); miR-7669 (SEQ ID NO:4541); miR-7670 (SEQ ID NO:4542); miR-7671 (SEQ ID NO:4543); miR-7672 (SEQ ID NO:4544); miR-7673 (SEQ ID NO:4545); miR-7674 (SEQ ID NO:4546); miR-7675 (SEQ ID NO:4547); miR-7676-1 (SEQ ID NO:4548); miR-7676-2 (SEQ ID NO:4549); miR-7677 (SEQ ID NO:4550); miR-7678 (SEQ ID NO:4551); miR-7679 (SEQ ID NO:4552); miR-7680 (SEQ ID NO:4553); miR-7681 (SEQ ID NO:4554); miR-7682 (SEQ ID NO:4555); miR-7683 (SEQ ID NO:4556); miR-7684 (SEQ ID NO:4557); miR-7685 (SEQ ID NO:4558); miR-7686 (SEQ ID NO:4559); miR-7687 (SEQ ID NO:4560); miR-7688 (SEQ ID NO:4561); miR-7689 (SEQ ID NO:4562); miR-8090 (SEQ ID NO:4563); miR-8091 (SEQ ID NO:4564); miR-8092 (SEQ ID NO:4565); miR-8093 (SEQ ID NO:4566); miR-8094 (SEQ ID NO:4567); miR-8095 (SEQ ID NO:4568); miR-8096 (SEQ ID NO:4569); miR-8097 (SEQ ID NO:4570); miR-8098 (SEQ ID NO:4571); miR-8099-1 (SEQ ID NO:4572); miR-8099-2 (SEQ ID NO:4573); miR-8100 (SEQ ID NO:4574); miR-8101 (SEQ ID NO:4575); miR-8102 (SEQ ID NO:4576); miR-8103 (SEQ ID NO:4577); miR-8104 (SEQ ID NO:4578); miR-8105 (SEQ ID NO:4579); miR-8106 (SEQ ID NO:4580); miR-8107 (SEQ ID NO:4581); miR-8108 (SEQ ID NO:4582); miR-8109 (SEQ ID NO:4583); miR-8110 (SEQ ID NO:4584); miR-8111 (SEQ ID NO:4585); miR-8112 (SEQ ID NO:4586); miR-8113 (SEQ ID NO:4587); miR-8114 (SEQ ID NO:4588); miR-8115 (SEQ ID NO:4589); miR-8116 (SEQ ID NO:4590); miR-8117 (SEQ ID NO:4591); miR-8118 (SEQ ID NO:4592); miR-8119 (SEQ ID NO:4593); and miR-8120 (SEQ ID NO:4594).

The following rat miRNAs could be used: let-7a-1 (SEQ ID NO:4595); let-7a-2 (SEQ ID NO:4596); let-7b (SEQ ID NO:4597); let-7c-1 (SEQ ID NO:4598); let-7c-2 (SEQ ID NO:4599); let-7d (SEQ ID NO:4600); let-7e (SEQ ID NO:4601); let-7f-1 (SEQ ID NO:4602); let-7f-2 (SEQ ID NO:4603); let-7i (SEQ ID NO:4604); miR-1 (SEQ ID NO:4605); miR-7a-1 (SEQ ID NO:4606); miR-7a-2 (SEQ ID NO:4607); miR-7b (SEQ ID NO:4608); miR-9a-1 (SEQ ID NO:4609); miR-9a-2 (SEQ ID NO:4610); miR-9a-3 (SEQ ID NO:4611); miR-9b-1 (SEQ ID NO:4612); miR-9b-2 (SEQ ID NO:4613); miR-9b-3 (SEQ ID NO:4614); miR-10a (SEQ ID NO:4615); miR-10b (SEQ ID NO:4616); miR-15b (SEQ ID NO:4617); miR-16 (SEQ ID NO:4618); miR-17-1 (SEQ ID NO:4619); miR-17-2 (SEQ ID NO:4620); miR-18a (SEQ ID NO:4621); miR-19a (SEQ ID NO:4622); miR-19b-1 (SEQ ID NO:4623); miR-19b-2 (SEQ ID NO:4624); miR-20a (SEQ ID NO:4625); miR-20b (SEQ ID NO:4626); miR-21 (SEQ ID NO:4627); miR-22 (SEQ ID NO:4628); miR-23a (SEQ ID NO:4629); miR-23b (SEQ ID NO:4630); miR-24-1 (SEQ ID NO:4631); miR-24-2 (SEQ ID NO:4632); miR-25 (SEQ ID NO:4633); miR-26a (SEQ ID NO:4634); miR-26b (SEQ ID NO:4635); miR-27a (SEQ ID NO:4636); miR-27b (SEQ ID NO:4637); miR-28 (SEQ ID NO:4638); miR-29a (SEQ ID NO:4639); miR-29b-1 (SEQ ID NO:4640); miR-29b-2 (SEQ ID NO:4641); miR-29c (SEQ ID NO:4642); miR-30a (SEQ ID NO:4643); miR-30b (SEQ ID NO:4644); miR-30c-1 (SEQ ID NO:4645); miR-30c-2 (SEQ ID NO:4646); miR-30d (SEQ ID NO:4647); miR-30e (SEQ ID NO:4648); miR-31a (SEQ ID NO:4649); miR-31b (SEQ ID NO:4650); miR-32 (SEQ ID NO:4651); miR-33 (SEQ ID NO:4652); miR-34a (SEQ ID NO:4653); miR-34b (SEQ ID NO:4654); miR-34c (SEQ ID NO:4655); miR-92a-1 (SEQ ID NO:4656); miR-92a-2 (SEQ ID NO:4657); miR-92b (SEQ ID NO:4658); miR-93 (SEQ ID NO:4659); miR-96 (SEQ ID NO:4660); miR-98 (SEQ ID NO:4661); miR-99a (SEQ ID NO:4662); miR-99b (SEQ ID NO:4663); miR-100 (SEQ ID NO:4664); miR-101a (SEQ ID NO:4665); miR-101b (SEQ ID NO:4666); miR-103-1 (SEQ ID NO:4667); miR-103-2 (SEQ ID NO:4668); miR-105 (SEQ ID NO:4669); miR-106b (SEQ ID NO:4670); miR-107 (SEQ ID NO:4671); miR-122 (SEQ ID NO:4672); miR-124-1 (SEQ ID NO:4673); miR-124-2 (SEQ ID NO:4674); miR-124-3 (SEQ ID NO:4675); miR-125a (SEQ ID NO:4676); miR-125b-1 (SEQ ID NO:4677); miR-125b-2 (SEQ ID NO:4678); miR-126a (SEQ ID NO:4679); miR-126b (SEQ ID NO:4680); miR-127 (SEQ ID NO:4681); miR-128-1 (SEQ ID NO:4682); miR-128-2 (SEQ ID NO:4683); miR-129-1 (SEQ ID NO:4684); miR-129-2 (SEQ ID NO:4685); miR-130a (SEQ ID NO:4686); miR-130b (SEQ ID NO:4687); miR-132 (SEQ ID NO:4688); miR-133a (SEQ ID NO:4689); miR-133b (SEQ ID NO:4690); miR-133c (SEQ ID NO:4691); miR-134 (SEQ ID NO:4692); miR-135a (SEQ ID NO:4693); miR-135b (SEQ ID NO:4694); miR-136 (SEQ ID NO:4695); miR-137 (SEQ ID NO:4696); miR-138-1 (SEQ ID NO:4697); miR-138-2 (SEQ ID NO:4698); miR-139 (SEQ ID NO:4699); miR-140 (SEQ ID NO:4700); miR-141 (SEQ ID NO:4701); miR-142 (SEQ ID NO:4702); miR-143 (SEQ ID NO:4703); miR-144 (SEQ ID NO:4704); miR-145 (SEQ ID NO:4705); miR-146a (SEQ ID NO:4706); miR-146b (SEQ ID NO:4707); miR-147 (SEQ ID NO:4708); miR-148b (SEQ ID NO:4709); miR-150 (SEQ ID NO:4710); miR-151 (SEQ ID NO:4711); miR-152 (SEQ ID NO:4712); miR-153 (SEQ ID NO:4713); miR-154 (SEQ ID NO:4714); miR-155 (SEQ ID NO:4715); miR-181a-1 (SEQ ID NO:4716); miR-181a-2 (SEQ ID NO:4717); miR-181b-1 (SEQ ID NO:4718); miR-181b-2 (SEQ ID NO:4719); miR-181c (SEQ ID NO:4720); miR-181d (SEQ ID NO:4721); miR-182 (SEQ ID NO:4722); miR-183 (SEQ ID NO:4723); miR-184 (SEQ ID NO:4724); miR-185 (SEQ ID NO:4725); miR-186 (SEQ ID NO:4726); miR-187 (SEQ ID NO:4727); miR-188 (SEQ ID NO:4728); miR-190a (SEQ ID NO:4729); miR-190b (SEQ ID NO:4730); miR-191a (SEQ ID NO:4731); miR-191b (SEQ ID NO:4732); miR-192 (SEQ ID NO:4733); miR-193 (SEQ ID NO:4734); miR-194-1 (SEQ ID NO:4735); miR-194-2 (SEQ ID NO:4736); miR-195 (SEQ ID NO:4737); miR-196a (SEQ ID NO:4738); miR-196b (SEQ ID NO:4739); miR-196c (SEQ ID NO:4740); miR-199a (SEQ ID NO:4741); miR-200a (SEQ ID NO:4742); miR-200b (SEQ ID NO:4743); miR-200c (SEQ ID NO:4744); miR-201 (SEQ ID NO:4745); miR-202 (SEQ ID NO:4746); miR-203a (SEQ ID NO:4747); miR-203b (SEQ ID NO:4748); miR-204 (SEQ ID NO:4749); miR-205 (SEQ ID NO:4750); miR-206 (SEQ ID NO:4751); miR-207 (SEQ ID NO:4752); miR-208a (SEQ ID NO:4753); miR-208b (SEQ ID NO:4754); miR-210 (SEQ ID NO:4755); miR-211 (SEQ ID NO:4756); miR-212 (SEQ ID NO:4757); miR-214 (SEQ ID NO:4758); miR-215 (SEQ ID NO:4759); miR-216a (SEQ ID NO:4760); miR-216b (SEQ ID NO:4761); miR-217 (SEQ ID NO:4762); miR-218a-1 (SEQ ID NO:4763); miR-218a-2 (SEQ ID NO:4764); miR-218b (SEQ ID NO:4765); miR-219a-1 (SEQ ID NO:4766); miR-219a-2 (SEQ ID NO:4767); miR-219b (SEQ ID NO:4768); miR-221 (SEQ ID NO:4769); miR-222 (SEQ ID NO:4770); miR-223 (SEQ ID NO:4771); miR-224 (SEQ ID NO:4772); miR-290 (SEQ ID NO:4773); miR-291a (SEQ ID NO:4774); miR-291b (SEQ ID NO:4775); miR-292 (SEQ ID NO:4776); miR-293 (SEQ ID NO:4777); miR-294 (SEQ ID NO:4778); miR-295-1 (SEQ ID NO:4779); miR-295-2 (SEQ ID NO:4780); miR-296 (SEQ ID NO:4781); miR-297 (SEQ ID NO:4782); miR-298 (SEQ ID NO:4783); miR-299a (SEQ ID NO:4784); miR-299b (SEQ ID NO:4785); miR-300 (SEQ ID NO:4786); miR-301a (SEQ ID NO:4787); miR-301b (SEQ ID NO:4788); miR-320 (SEQ ID NO:4789); miR-322 (SEQ ID NO:4790); miR-323 (SEQ ID NO:4791); miR-324 (SEQ ID NO:4792); miR-325 (SEQ ID NO:4793); miR-326 (SEQ ID NO:4794); miR-327 (SEQ ID NO:4795); miR-328a (SEQ ID NO:4796); miR-328b (SEQ ID NO:4797); miR-329 (SEQ ID NO:4798); miR-330 (SEQ ID NO:4799); miR-331 (SEQ ID NO:4800); miR-335 (SEQ ID NO:4801); miR-336 (SEQ ID NO:4802); miR-337 (SEQ ID NO:4803); miR-338 (SEQ ID NO:4804); miR-339 (SEQ ID NO:4805); miR-340 (SEQ ID NO:4806); miR-341 (SEQ ID NO:4807); miR-342 (SEQ ID NO:4808); miR-343 (SEQ ID NO:4809); miR-344a-1 (SEQ ID NO:4810); miR-344a-2 (SEQ ID NO:4811); miR-344b-1 (SEQ ID NO:4812); miR-344b-2 (SEQ ID NO:4813); miR-344g (SEQ ID NO:4814); miR-344i (SEQ ID NO:4815); miR-345 (SEQ ID NO:4816); miR-346 (SEQ ID NO:4817); miR-347 (SEQ ID NO:4818); miR-349 (SEQ ID NO:4819); miR-350 (SEQ ID NO:4820); miR-351 (SEQ ID NO:4821); miR-352 (SEQ ID NO:4822); miR-361 (SEQ ID NO:4823); miR-362 (SEQ ID NO:4824); miR-363 (SEQ ID NO:4825); miR-365 (SEQ ID NO:4826); miR-369 (SEQ ID NO:4827); miR-370 (SEQ ID NO:4828); miR-374 (SEQ ID NO:4829); miR-375 (SEQ ID NO:4830); miR-376a (SEQ ID NO:4831); miR-376b (SEQ ID NO:4832); miR-376c (SEQ ID NO:4833); miR-377 (SEQ ID NO:4834); miR-378a (SEQ ID NO:4835); miR-378b (SEQ ID NO:4836); miR-379 (SEQ ID NO:4837); miR-380 (SEQ ID NO:4838); miR-381 (SEQ ID NO:4839); miR-382 (SEQ ID NO:4840); miR-383 (SEQ ID NO:4841); miR-384 (SEQ ID NO:4842); miR-409a (SEQ ID NO:4843); miR-409b (SEQ ID NO:4844); miR-410 (SEQ ID NO:4845); miR-411 (SEQ ID NO:4846); miR-412 (SEQ ID NO:4847); miR-421 (SEQ ID NO:4848); miR-423 (SEQ ID NO:4849); miR-425 (SEQ ID NO:4850); miR-429 (SEQ ID NO:4851); miR-431 (SEQ ID NO:4852); miR-433 (SEQ ID NO:4853); miR-434 (SEQ ID NO:4854); miR-448 (SEQ ID NO:4855); miR-449a (SEQ ID NO:4856); miR-449c (SEQ ID NO:4857); miR-450a (SEQ ID NO:4858); miR-451 (SEQ ID NO:4859); miR-455 (SEQ ID NO:4860); miR-463 (SEQ ID NO:4861); miR-465 (SEQ ID NO:4862); miR-466b-1 (SEQ ID NO:4863); miR-466b-2 (SEQ ID NO:4864); miR-466c (SEQ ID NO:4865); miR-466d (SEQ ID NO:4866); miR-471 (SEQ ID NO:4867); miR-483 (SEQ ID NO:4868); miR-484 (SEQ ID NO:4869); miR-485 (SEQ ID NO:4870); miR-487b (SEQ ID NO:4871); miR-488 (SEQ ID NO:4872); miR-489 (SEQ ID NO:4873); miR-490 (SEQ ID NO:4874); miR-493 (SEQ ID NO:4875); miR-494 (SEQ ID NO:4876); miR-495 (SEQ ID NO:4877); miR-496 (SEQ ID NO:4878); miR-497 (SEQ ID NO:4879); miR-499 (SEQ ID NO:4880); miR-500 (SEQ ID NO:4881); miR-501 (SEQ ID NO:4882); miR-503 (SEQ ID NO:4883); miR-504 (SEQ ID NO:4884); miR-505 (SEQ ID NO:4885); miR-509 (SEQ ID NO:4886); miR-511 (SEQ ID NO:4887); miR-532 (SEQ ID NO:4888); miR-539 (SEQ ID NO:4889); miR-540 (SEQ ID NO:4890); miR-541 (SEQ ID NO:4891); miR-542 (SEQ ID NO:4892); miR-543 (SEQ ID NO:4893); miR-544 (SEQ ID NO:4894); miR-547 (SEQ ID NO:4895); miR-551b (SEQ ID NO:4896); miR-568 (SEQ ID NO:4897); miR-582 (SEQ ID NO:4898); miR-592 (SEQ ID NO:4899); miR-598 (SEQ ID NO:4900); miR-615 (SEQ ID NO:4901); miR-628 (SEQ ID NO:4902); miR-632 (SEQ ID NO:4903); miR-652 (SEQ ID NO:4904); miR-653 (SEQ ID NO:4905); miR-664-1 (SEQ ID NO:4906); miR-664-2 (SEQ ID NO:4907); miR-665 (SEQ ID NO:4908); miR-666 (SEQ ID NO:4909); miR-667 (SEQ ID NO:4910); miR-668 (SEQ ID NO:4911); miR-671 (SEQ ID NO:4912); miR-672 (SEQ ID NO:4913); miR-673 (SEQ ID NO:4914); miR-674 (SEQ ID NO:4915); miR-675 (SEQ ID NO:4916); miR-678 (SEQ ID NO:4917); miR-679 (SEQ ID NO:4918); miR-702 (SEQ ID NO:4919); miR-708 (SEQ ID NO:4920); miR-711 (SEQ ID NO:4921); miR-741 (SEQ ID NO:4922); miR-742 (SEQ ID NO:4923); miR-743a (SEQ ID NO:4924); miR-743b (SEQ ID NO:4925); miR-758 (SEQ ID NO:4926); miR-759 (SEQ ID NO:4927); miR-760 (SEQ ID NO:4928); miR-761 (SEQ ID NO:4929); miR-764 (SEQ ID NO:4930); miR-770 (SEQ ID NO:4931); miR-802 (SEQ ID NO:4932); miR-871 (SEQ ID NO:4933); miR-872 (SEQ ID NO:4934); miR-873 (SEQ ID NO:4935); miR-874 (SEQ ID NO:4936); miR-875 (SEQ ID NO:4937); miR-876 (SEQ ID NO:4938); miR-877 (SEQ ID NO:4939); miR-878 (SEQ ID NO:4940); miR-879 (SEQ ID NO:4941); miR-880 (SEQ ID NO:4942); miR-881 (SEQ ID NO:4943); miR-883 (SEQ ID NO:4944); miR-935 (SEQ ID NO:4945); miR-1188 (SEQ ID NO:4946); miR-1193 (SEQ ID NO:4947); miR-1199 (SEQ ID NO:4948); miR-1224 (SEQ ID NO:4949); miR-1249 (SEQ ID NO:4950); miR-1298 (SEQ ID NO:4951); miR-1306 (SEQ ID NO:4952); miR-1839 (SEQ ID NO:4953); miR-1843 (SEQ ID NO:4954); miR-1912 (SEQ ID NO:4955); miR-1949 (SEQ ID NO:4956); miR-2985 (SEQ ID NO:4957); miR-3065 (SEQ ID NO:4958); miR-3068 (SEQ ID NO:4959); miR-3072 (SEQ ID NO:4960); miR-3074 (SEQ ID NO:4961); miR-3075 (SEQ ID NO:4962); miR-3085 (SEQ ID NO:4963); miR-3099 (SEQ ID NO:4964); miR-3102 (SEQ ID NO:4965); miR-3120 (SEQ ID NO:4966); miR-3473 (SEQ ID NO:4967); miR-3541 (SEQ ID NO:4968); miR-3542 (SEQ ID NO:4969); miR-3543 (SEQ ID NO:4970); miR-3544 (SEQ ID NO:4971); miR-3546 (SEQ ID NO:4972); miR-3547 (SEQ ID NO:4973); miR-3548 (SEQ ID NO:4974); miR-3549 (SEQ ID NO:4975); miR-3550 (SEQ ID NO:4976); miR-3551 (SEQ ID NO:4977); miR-3552 (SEQ ID NO:4978); miR-3553 (SEQ ID NO:4979); miR-3556a (SEQ ID NO:4980); miR-3556b (SEQ ID NO:4981); miR-3557 (SEQ ID NO:4982); miR-3558 (SEQ ID NO:4983); miR-3559 (SEQ ID NO:4984); miR-3560 (SEQ ID NO:4985); miR-3561 (SEQ ID NO:4986); miR-3562 (SEQ ID NO:4987); miR-3564 (SEQ ID NO:4988); miR-3566 (SEQ ID NO:4989); miR-3568 (SEQ ID NO:4990); miR-3569 (SEQ ID NO:4991); miR-3570 (SEQ ID NO:4992); miR-3571 (SEQ ID NO:4993); miR-3572 (SEQ ID NO:4994); miR-3573 (SEQ ID NO:4995); miR-3574 (SEQ ID NO:4996); miR-3575 (SEQ ID NO:4997); miR-3576 (SEQ ID NO:4998); miR-3577 (SEQ ID NO:4999); miR-3578 (SEQ ID NO:5000); miR-3579 (SEQ ID NO:5001); miR-3580 (SEQ ID NO:5002); miR-3583 (SEQ ID NO:5003); miR-3584 (SEQ ID NO:5004); miR-3585 (SEQ ID NO:5005); miR-3586 (SEQ ID NO:5006); miR-3587 (SEQ ID NO:5007); miR-3588 (SEQ ID NO:5008); miR-3589 (SEQ ID NO:5009); miR-3590 (SEQ ID NO:5010); miR-3591 (SEQ ID NO:5011); miR-3592 (SEQ ID NO:5012); miR-3593 (SEQ ID NO:5013); miR-3594 (SEQ ID NO:5014); miR-3595 (SEQ ID NO:5015); miR-3596a (SEQ ID NO:5016); miR-3596b (SEQ ID NO:5017); miR-3596c (SEQ ID NO:5018); miR-3596d (SEQ ID NO:5019); miR-6215 (SEQ ID NO:5020); miR-6216 (SEQ ID NO:5021); miR-6314 (SEQ ID NO:5022); miR-6315 (SEQ ID NO:5023); miR-6316 (SEQ ID NO:5024); miR-6317 (SEQ ID NO:5025); miR-6318 (SEQ ID NO:5026); miR-6319 (SEQ ID NO:5027); miR-6320 (SEQ ID NO:5028); miR-6321 (SEQ ID NO:5029); miR-6322 (SEQ ID NO:5030); miR-6323 (SEQ ID NO:5031); miR-6324 (SEQ ID NO:5032); miR-6325 (SEQ ID NO:5033); miR-6326 (SEQ ID NO:5034); miR-6327 (SEQ ID NO:5035); miR-6328 (SEQ ID NO:5036); miR-6329 (SEQ ID NO:5037); miR-6330 (SEQ ID NO:5038); miR-6331 (SEQ ID NO:5039); miR-6332 (SEQ ID NO:5040); miR-6333 (SEQ ID NO:5041); miR-6334 (SEQ ID NO:5042); and miR-7578 (SEQ ID NO:5043).

The following fruit fly miRNAs could be used: bantam (SEQ ID NO:5044); let-7 (SEQ ID NO:5045); miR-1 (SEQ ID NO:5046); miR-2a-1 (SEQ ID NO:5047); miR-2a-2 (SEQ ID NO:5048); miR-2b-1 (SEQ ID NO:5049); miR-2b-2 (SEQ ID NO:5050); miR-2c (SEQ ID NO:5051); miR-3 (SEQ ID NO:5052); miR-4 (SEQ ID NO:5053); miR-5 (SEQ ID NO:5054); miR-6-1 (SEQ ID NO:5055); miR-6-2 (SEQ ID NO:5056); miR-6-3 (SEQ ID NO:5057); miR-7 (SEQ ID NO:5058); miR-8 (SEQ ID NO:5059); miR-9a (SEQ ID NO:5060); miR-9b (SEQ ID NO:5061); miR-9c (SEQ ID NO:5062); miR-10 (SEQ ID NO:5063); miR-11 (SEQ ID NO:5064); miR-12 (SEQ ID NO:5065); miR-13a (SEQ ID NO:5066); miR-13b-1 (SEQ ID NO:5067); miR-13b-2 (SEQ ID NO:5068); miR-14 (SEQ ID NO:5069); miR-31a (SEQ ID NO:5070); miR-31b (SEQ ID NO:5071); miR-33 (SEQ ID NO:5072); miR-34 (SEQ ID NO:5073); miR-79 (SEQ ID NO:5074); miR-87 (SEQ ID NO:5075); miR-92a (SEQ ID NO:5076); miR-92b (SEQ ID NO:5077); miR-100 (SEQ ID NO:5078); miR-124 (SEQ ID NO:5079); miR-125 (SEQ ID NO:5080); miR-133 (SEQ ID NO:5081); miR-137 (SEQ ID NO:5082); miR-184 (SEQ ID NO:5083); miR-190 (SEQ ID NO:5084); miR-193 (SEQ ID NO:5085); miR-210 (SEQ ID NO:5086); miR-219 (SEQ ID NO:5087); miR-252 (SEQ ID NO:5088); miR-263a (SEQ ID NO:5089); miR-263b (SEQ ID NO:5090); miR-274 (SEQ ID NO:5091); miR-275 (SEQ ID NO:5092); miR-276a (SEQ ID NO:5093); miR-276b (SEQ ID NO:5094); miR-277 (SEQ ID NO:5095); miR-278 (SEQ ID NO:5096); miR-279 (SEQ ID NO:5097); miR-280 (SEQ ID NO:5098); miR-281-1 (SEQ ID NO:5099); miR-281-2 (SEQ ID NO:5100); miR-282 (SEQ ID NO:5101); miR-283 (SEQ ID NO:5102); miR-284 (SEQ ID NO:5103); miR-285 (SEQ ID NO:5104); miR-286 (SEQ ID NO:5105); miR-287 (SEQ ID NO:5106); miR-288 (SEQ ID NO:5107); miR-289 (SEQ ID NO:5108); miR-303 (SEQ ID NO:5109); miR-304 (SEQ ID NO:5110); miR-305 (SEQ ID NO:5111); miR-306 (SEQ ID NO:5112); miR-307a (SEQ ID NO:5113); miR-307b (SEQ ID NO:5114); miR-308 (SEQ ID NO:5115); miR-309 (SEQ ID NO:5116); miR-310 (SEQ ID NO:5117); miR-311 (SEQ ID NO:5118); miR-312 (SEQ ID NO:5119); miR-313 (SEQ ID NO:5120); miR-314 (SEQ ID NO:5121); miR-315 (SEQ ID NO:5122); miR-316 (SEQ ID NO:5123); miR-317 (SEQ ID NO:5124); miR-318 (SEQ ID NO:5125); miR-375 (SEQ ID NO:5126); miR-927 (SEQ ID NO:5127); miR-929 (SEQ ID NO:5128); miR-932 (SEQ ID NO:5129); miR-954 (SEQ ID NO:5130); miR-955 (SEQ ID NO:5131); miR-956 (SEQ ID NO:5132); miR-957 (SEQ ID NO:5133); miR-958 (SEQ ID NO:5134); miR-959 (SEQ ID NO:5135); miR-960 (SEQ ID NO:5136); miR-961 (SEQ ID NO:5137); miR-962 (SEQ ID NO:5138); miR-963 (SEQ ID NO:5139); miR-964 (SEQ ID NO:5140); miR-965 (SEQ ID NO:5141); miR-966 (SEQ ID NO:5142); miR-967 (SEQ ID NO:5143); miR-968 (SEQ ID NO:5144); miR-969 (SEQ ID NO:5145); miR-970 (SEQ ID NO:5146); miR-971 (SEQ ID NO:5147); miR-972 (SEQ ID NO:5148); miR-973 (SEQ ID NO:5149); miR-974 (SEQ ID NO:5150); miR-975 (SEQ ID NO:5151); miR-976 (SEQ ID NO:5152); miR-977 (SEQ ID NO:5153); miR-978 (SEQ ID NO:5154); miR-979 (SEQ ID NO:5155); miR-980 (SEQ ID NO:5156); miR-981 (SEQ ID NO:5157); miR-982 (SEQ ID NO:5158); miR-983-1 (SEQ ID NO:5159); miR-983-2 (SEQ ID NO:5160); miR-984 (SEQ ID NO:5161); miR-985 (SEQ ID NO:5162); miR-986 (SEQ ID NO:5163); miR-987 (SEQ ID NO:5164); miR-988 (SEQ ID NO:5165); miR-989 (SEQ ID NO:5166); miR-990 (SEQ ID NO:5167); miR-991 (SEQ ID NO:5168); miR-992 (SEQ ID NO:5169); miR-993 (SEQ ID NO:5170); miR-994 (SEQ ID NO:5171); miR-995 (SEQ ID NO:5172); miR-996 (SEQ ID NO:5173); miR-997 (SEQ ID NO:5174); miR-998 (SEQ ID NO:5175); miR-999 (SEQ ID NO:5176); miR-1000 (SEQ ID NO:5177); miR-1001 (SEQ ID NO:5178); miR-1002 (SEQ ID NO:5179); miR-1003 (SEQ ID NO:5180); miR-1004 (SEQ ID NO:5181); miR-1005 (SEQ ID NO:5182); miR-1006 (SEQ ID NO:5183); miR-1007 (SEQ ID NO:5184); miR-1008 (SEQ ID NO:5185); miR-1009 (SEQ ID NO:5186); miR-1010 (SEQ ID NO:5187); miR-1011 (SEQ ID NO:5188); miR-1012 (SEQ ID NO:5189); miR-1013 (SEQ ID NO:5190); miR-1014 (SEQ ID NO:5191); miR-1015 (SEQ ID NO:5192); miR-1016 (SEQ ID NO:5193); miR-1017 (SEQ ID NO:5194); miR-2279 (SEQ ID NO:5195); miR-2280 (SEQ ID NO:5196); miR-2281 (SEQ ID NO:5197); miR-2282 (SEQ ID NO:5198); miR-2283 (SEQ ID NO:5199); miR-2489 (SEQ ID NO:5200); miR-2490 (SEQ ID NO:5201); miR-2491 (SEQ ID NO:5202); miR-2492 (SEQ ID NO:5203); miR-2493 (SEQ ID NO:5204); miR-2494 (SEQ ID NO:5205); miR-2495 (SEQ ID NO:5206); miR-2496 (SEQ ID NO:5207); miR-2497 (SEQ ID NO:5208); miR-2498 (SEQ ID NO:5209); miR-2499 (SEQ ID NO:5210); miR-2500 (SEQ ID NO:5211); miR-2501 (SEQ ID NO:5212); miR-2535b (SEQ ID NO:5213); miR-3641 (SEQ ID NO:5214); miR-3642 (SEQ ID NO:5215); miR-3643 (SEQ ID NO:5216); miR-3644 (SEQ ID NO:5217); miR-3645 (SEQ ID NO:5218); miR-4908 (SEQ ID NO:5219); miR-4909 (SEQ ID NO:5220); miR-4910 (SEQ ID NO:5221); miR-4911 (SEQ ID NO:5222); miR-4912 (SEQ ID NO:5223); miR-4913 (SEQ ID NO:5224); miR-4914 (SEQ ID NO:5225); miR-4915 (SEQ ID NO:5226); miR-4916 (SEQ ID NO:5227); miR-4917 (SEQ ID NO:5228); miR-4918 (SEQ ID NO:5229); miR-4919 (SEQ ID NO:5230); miR-4939 (SEQ ID NO:5231); miR-4940 (SEQ ID NO:5232); miR-4941 (SEQ ID NO:5233); miR-4942 (SEQ ID NO:5234); miR-4943 (SEQ ID NO:5235); miR-4944 (SEQ ID NO:5236); miR-4945 (SEQ ID NO:5237); miR-4946 (SEQ ID NO:5238); miR-4947 (SEQ ID NO:5239); miR-4948 (SEQ ID NO:5240); miR-4949 (SEQ ID NO:5241); miR-4950 (SEQ ID NO:5242); miR-4951 (SEQ ID NO:5243); miR-4952 (SEQ ID NO:5244); miR-4953 (SEQ ID NO:5245); miR-4954 (SEQ ID NO:5246); miR-4955 (SEQ ID NO:5247); miR-4956 (SEQ ID NO:5248); miR-4957 (SEQ ID NO:5249); miR-4958 (SEQ ID NO:5250); miR-4959 (SEQ ID NO:5251); miR-4960 (SEQ ID NO:5252); miR-4961 (SEQ ID NO:5253); miR-4962 (SEQ ID NO:5254); miR-4963 (SEQ ID NO:5255); miR-4964 (SEQ ID NO:5256); miR-4965 (SEQ ID NO:5257); miR-4966 (SEQ ID NO:5258); miR-4967 (SEQ ID NO:5259); miR-4968 (SEQ ID NO:5260); miR-4969 (SEQ ID NO:5261); miR-4970 (SEQ ID NO:5262); miR-4971 (SEQ ID NO:5263); miR-4972 (SEQ ID NO:5264); miR-4973 (SEQ ID NO:5265); miR-4974 (SEQ ID NO:5266); miR-4975 (SEQ ID NO:5267); miR-4976 (SEQ ID NO:5268); miR-4977 (SEQ ID NO:5269); miR-4978 (SEQ ID NO:5270); miR-4979 (SEQ ID NO:5271); miR-4980 (SEQ ID NO:5272); miR-4981 (SEQ ID NO:5273); miR-4982 (SEQ ID NO:5274); miR-4983 (SEQ ID NO:5275); miR-4984 (SEQ ID NO:5276); miR-4985 (SEQ ID NO:5277); miR-4986 (SEQ ID NO:5278); miR-4987 (SEQ ID NO:5279); miR-iab-4 (SEQ ID NO:5280); and miR-iab-8 (SEQ ID NO:5281).

The following cow miRNA could be used: let-7a-1 (SEQ ID NO:5282); let-7a-2 (SEQ ID NO:5283); let-7a-3 (SEQ ID NO:5284); let-7b (SEQ ID NO:5285); let-7c (SEQ ID NO:5286); let-7d (SEQ ID NO:5287); let-7e (SEQ ID NO:5288); let-7f-1 (SEQ ID NO:5289); let-7f-2 (SEQ ID NO:5290); let-7g (SEQ ID NO:5291); let-7i (SEQ ID NO:5292); miR-1-1 (SEQ ID NO:5293); miR-1-2 (SEQ ID NO:5294); miR-7-1 (SEQ ID NO:5295); miR-7-2 (SEQ ID NO:5296); miR-7-3 (SEQ ID NO:5297); miR-9-1 (SEQ ID NO:5298); miR-9-2 (SEQ ID NO:5299); miR-10a (SEQ ID NO:5300); miR-10b (SEQ ID NO:5301); miR-15a (SEQ ID NO:5302); miR-15b (SEQ ID NO:5303); miR-16a (SEQ ID NO:5304); miR-16b (SEQ ID NO:5305); miR-17 (SEQ ID NO:5306); miR-18a (SEQ ID NO:5307); miR-18b (SEQ ID NO:5308); miR-19a (SEQ ID NO:5309); miR-19b (SEQ ID NO:5310); miR-19b-2 (SEQ ID NO:5311); miR-20a (SEQ ID NO:5312); miR-20b (SEQ ID NO:5313); miR-21 (SEQ ID NO:5314); miR-22 (SEQ ID NO:5315); miR-23a (SEQ ID NO:5316); miR-23b (SEQ ID NO:5317); miR-24-1 (SEQ ID NO:5318); miR-24-2 (SEQ ID NO:5319); miR-25 (SEQ ID NO:5320); miR-26a-1 (SEQ ID NO:5321); miR-26a-2 (SEQ ID NO:5322); miR-26b (SEQ ID NO:5323); miR-26c (SEQ ID NO:5324); miR-27a (SEQ ID NO:5325); miR-27b (SEQ ID NO:5326); miR-28 (SEQ ID NO:5327); miR-29a (SEQ ID NO:5328); miR-29b-1 (SEQ ID NO:5329); miR-29b-2 (SEQ ID NO:5330); miR-29c (SEQ ID NO:5331); miR-29d (SEQ ID NO:5332); miR-29e (SEQ ID NO:5333); miR-30a (SEQ ID NO:5334); miR-30b (SEQ ID NO:5335); miR-30c (SEQ ID NO:5336); miR-30d (SEQ ID NO:5337); miR-30e (SEQ ID NO:5338); miR-30f (SEQ ID NO:5339); miR-31 (SEQ ID NO:5340); miR-32 (SEQ ID NO:5341); miR-33a (SEQ ID NO:5342); miR-33b (SEQ ID NO:5343); miR-34a (SEQ ID NO:5344); miR-34b (SEQ ID NO:5345); miR-34c (SEQ ID NO:5346); miR-92a-1 (SEQ ID NO:5347); miR-92a-2 (SEQ ID NO:5348); miR-92b (SEQ ID NO:5349); miR-93 (SEQ ID NO:5350); miR-95 (SEQ ID NO:5351); miR-96 (SEQ ID NO:5352); miR-98 (SEQ ID NO:5353); miR-99a (SEQ ID NO:5354); miR-99b (SEQ ID NO:5355); miR-100 (SEQ ID NO:5356); miR-101-1 (SEQ ID NO:5357); miR-101-2 (SEQ ID NO:5358); miR-103-1 (SEQ ID NO:5359); miR-103-2 (SEQ ID NO:5360); miR-105a (SEQ ID NO:5361); miR-105b (SEQ ID NO:5362); miR-106a (SEQ ID NO:5363); miR-106b (SEQ ID NO:5364); miR-107 (SEQ ID NO:5365); miR-122 (SEQ ID NO:5366); miR-124a-1 (SEQ ID NO:5367); miR-124a-2 (SEQ ID NO:5368); miR-124b (SEQ ID NO:5369); miR-125a (SEQ ID NO:5370); miR-125b-1 (SEQ ID NO:5371); miR-125b-2 (SEQ ID NO:5372); miR-126 (SEQ ID NO:5373); miR-127 (SEQ ID NO:5374); miR-128-1 (SEQ ID NO:5375); miR-128-2 (SEQ ID NO:5376); miR-129-1 (SEQ ID NO:5377); miR-129-2 (SEQ ID NO:5378); miR-130a (SEQ ID NO:5379); miR-130b (SEQ ID NO:5380); miR-132 (SEQ ID NO:5381); miR-133a-1 (SEQ ID NO:5382); miR-133a-2 (SEQ ID NO:5383); miR-133b (SEQ ID NO:5384); miR-133c (SEQ ID NO:5385); miR-134 (SEQ ID NO:5386); miR-135a-1 (SEQ ID NO:5387); miR-135a-2 (SEQ ID NO:5388); miR-135b (SEQ ID NO:5389); miR-136 (SEQ ID NO:5390); miR-137 (SEQ ID NO:5391); miR-138-1 (SEQ ID NO:5392); miR-138-2 (SEQ ID NO:5393); miR-139 (SEQ ID NO:5394); miR-140 (SEQ ID NO:5395); miR-141 (SEQ ID NO:5396); miR-142 (SEQ ID NO:5397); miR-143 (SEQ ID NO:5398); miR-144 (SEQ ID NO:5399); miR-145 (SEQ ID NO:5400); miR-146a (SEQ ID NO:5401); miR-146b (SEQ ID NO:5402); miR-147 (SEQ ID NO:5403); miR-148a (SEQ ID NO:5404); miR-148b (SEQ ID NO:5405); miR-149 (SEQ ID NO:5406); miR-150 (SEQ ID NO:5407); miR-151 (SEQ ID NO:5408); miR-152 (SEQ ID NO:5409); miR-153-1 (SEQ ID NO:5410); miR-153-2 (SEQ ID NO:5411); miR-154a (SEQ ID NO:5412); miR-154b (SEQ ID NO:5413); miR-154c (SEQ ID NO:5414); miR-155 (SEQ ID NO:5415); miR-181a-1 (SEQ ID NO:5416); miR-181a-2 (SEQ ID NO:5417); miR-181b-1 (SEQ ID NO:5418); miR-181b-2 (SEQ ID NO:5419); miR-181c (SEQ ID NO:5420); miR-181d (SEQ ID NO:5421); miR-182 (SEQ ID NO:5422); miR-183 (SEQ ID NO:5423); miR-184 (SEQ ID NO:5424); miR-185 (SEQ ID NO:5425); miR-186 (SEQ ID NO:5426); miR-187 (SEQ ID NO:5427); miR-188 (SEQ ID NO:5428); miR-190a (SEQ ID NO:5429); miR-190b (SEQ ID NO:5430); miR-191 (SEQ ID NO:5431); miR-192 (SEQ ID NO:5432); miR-193a (SEQ ID NO:5433); miR-193a-2 (SEQ ID NO:5434); miR-193b (SEQ ID NO:5435); miR-194-1 (SEQ ID NO:5436); miR-194-2 (SEQ ID NO:5437); miR-195 (SEQ ID NO:5438); miR-196a-1 (SEQ ID NO:5439); miR-196a-2 (SEQ ID NO:5440); miR-196b (SEQ ID NO:5441); miR-197 (SEQ ID NO:5442); miR-199a-1 (SEQ ID NO:5443); miR-199a-2 (SEQ ID NO:5444); miR-199b (SEQ ID NO:5445); miR-199c (SEQ ID NO:5446); miR-200a (SEQ ID NO:5447); miR-200b (SEQ ID NO:5448); miR-200c (SEQ ID NO:5449); miR-202 (SEQ ID NO:5450); miR-204 (SEQ ID NO:5451); miR-205 (SEQ ID NO:5452); miR-206 (SEQ ID NO:5453); miR-208a (SEQ ID NO:5454); miR-208b (SEQ ID NO:5455); miR-210 (SEQ ID NO:5456); miR-211 (SEQ ID NO:5457); miR-212 (SEQ ID NO:5458); miR-214 (SEQ ID NO:5459); miR-215 (SEQ ID NO:5460); miR-216a (SEQ ID NO:5461); miR-216b (SEQ ID NO:5462); miR-217 (SEQ ID NO:5463); miR-218-1 (SEQ ID NO:5464); miR-218-2 (SEQ ID NO:5465); miR-219 (SEQ ID NO:5466); miR-219-2 (SEQ ID NO:5467); miR-221 (SEQ ID NO:5468); miR-222 (SEQ ID NO:5469); miR-223 (SEQ ID NO:5470); miR-224 (SEQ ID NO:5471); miR-296 (SEQ ID NO:5472); miR-299 (SEQ ID NO:5473); miR-301a (SEQ ID NO:5474); miR-301b (SEQ ID NO:5475); miR-302a (SEQ ID NO:5476); miR-302b (SEQ ID NO:5477); miR-302c (SEQ ID NO:5478); miR-302d (SEQ ID NO:5479); miR-320a-1 (SEQ ID NO:5480); miR-320a-2 (SEQ ID NO:5481); miR-320b (SEQ ID NO:5482); miR-323 (SEQ ID NO:5483); miR-324 (SEQ ID NO:5484); miR-326 (SEQ ID NO:5485); miR-328 (SEQ ID NO:5486); miR-329a (SEQ ID NO:5487); miR-329b (SEQ ID NO:5488); miR-330 (SEQ ID NO:5489); miR-331 (SEQ ID NO:5490); miR-335 (SEQ ID NO:5491); miR-338 (SEQ ID NO:5492); miR-339a (SEQ ID NO:5493); miR-339b (SEQ ID NO:5494); miR-340 (SEQ ID NO:5495); miR-342 (SEQ ID NO:5496); miR-345 (SEQ ID NO:5497); miR-346 (SEQ ID NO:5498); miR-361 (SEQ ID NO:5499); miR-362 (SEQ ID NO:5500); miR-363 (SEQ ID NO:5501); miR-365-1 (SEQ ID NO:5502); miR-365-2 (SEQ ID NO:5503); miR-367 (SEQ ID NO:5504); miR-369 (SEQ ID NO:5505); miR-370 (SEQ ID NO:5506); miR-371 (SEQ ID NO:5507); miR-374a (SEQ ID NO:5508); miR-374b (SEQ ID NO:5509); miR-375 (SEQ ID NO:5510); miR-376a (SEQ ID NO:5511); miR-376b (SEQ ID NO:5512); miR-376c (SEQ ID NO:5513); miR-376d (SEQ ID NO:5514); miR-376e (SEQ ID NO:5515); miR-377 (SEQ ID NO:5516); miR-378-1 (SEQ ID NO:5517); miR-378-2 (SEQ ID NO:5518); miR-378b (SEQ ID NO:5519); miR-378c (SEQ ID NO:5520); miR-379 (SEQ ID NO:5521); miR-380 (SEQ ID NO:5522); miR-381 (SEQ ID NO:5523); miR-382 (SEQ ID NO:5524); miR-383 (SEQ ID NO:5525); miR-409a (SEQ ID NO:5526); miR-409b (SEQ ID NO:5527); miR-410 (SEQ ID NO:5528); miR-411a (SEQ ID NO:5529); miR-411b (SEQ ID NO:5530); miR-411c (SEQ ID NO:5531); miR-412 (SEQ ID NO:5532); miR-421 (SEQ ID NO:5533); miR-423 (SEQ ID NO:5534); miR-424 (SEQ ID NO:5535); miR-425 (SEQ ID NO:5536); miR-429 (SEQ ID NO:5537); miR-431 (SEQ ID NO:5538); miR-432 (SEQ ID NO:5539); miR-433 (SEQ ID NO:5540); miR-448 (SEQ ID NO:5541); miR-449a (SEQ ID NO:5542); miR-449b (SEQ ID NO:5543); miR-449c (SEQ ID NO:5544); miR-449d (SEQ ID NO:5545); miR-450a-1 (SEQ ID NO:5546); miR-450a-2 (SEQ ID NO:5547); miR-450b (SEQ ID NO:5548); miR-451 (SEQ ID NO:5549); miR-452 (SEQ ID NO:5550); miR-453 (SEQ ID NO:5551); miR-454 (SEQ ID NO:5552); miR-455 (SEQ ID NO:5553); miR-483 (SEQ ID NO:5554); miR-484 (SEQ ID NO:5555); miR-485 (SEQ ID NO:5556); miR-486 (SEQ ID NO:5557); miR-487a (SEQ ID NO:5558); miR-487b (SEQ ID NO:5559); miR-488 (SEQ ID NO:5560); miR-489 (SEQ ID NO:5561); miR-490 (SEQ ID NO:5562); miR-491 (SEQ ID NO:5563); miR-493 (SEQ ID NO:5564); miR-494 (SEQ ID NO:5565); miR-495 (SEQ ID NO:5566); miR-496 (SEQ ID NO:5567); miR-497 (SEQ ID NO:5568); miR-499 (SEQ ID NO:5569); miR-500 (SEQ ID NO:5570); miR-502a-1 (SEQ ID NO:5571); miR-502a-2 (SEQ ID NO:5572); miR-502b (SEQ ID NO:5573); miR-503 (SEQ ID NO:5574); miR-504 (SEQ ID NO:5575); miR-505 (SEQ ID NO:5576); miR-532 (SEQ ID NO:5577); miR-539 (SEQ ID NO:5578); miR-541 (SEQ ID NO:5579); miR-542 (SEQ ID NO:5580); miR-543 (SEQ ID NO:5581); miR-544a (SEQ ID NO:5582); miR-544b-1 (SEQ ID NO:5583); miR-544b-2 (SEQ ID NO:5584); miR-545 (SEQ ID NO:5585); miR-551a (SEQ ID NO:5586); miR-551b (SEQ ID NO:5587); miR-562 (SEQ ID NO:5588); miR-568 (SEQ ID NO:5589); miR-574 (SEQ ID NO:5590); miR-582 (SEQ ID NO:5591); miR-584-1 (SEQ ID NO:5592); miR-584-2 (SEQ ID NO:5593); miR-584-3 (SEQ ID NO:5594); miR-584-4 (SEQ ID NO:5595); miR-584-5 (SEQ ID NO:5596); miR-584-6 (SEQ ID NO:5597); miR-584-7 (SEQ ID NO:5598); miR-584-8 (SEQ ID NO:5599); miR-592 (SEQ ID NO:5600); miR-599 (SEQ ID NO:5601); miR-615 (SEQ ID NO:5602); miR-628 (SEQ ID NO:5603); miR-631 (SEQ ID NO:5604); miR-652 (SEQ ID NO:5605); miR-653 (SEQ ID NO:5606); miR-654 (SEQ ID NO:5607); miR-655 (SEQ ID NO:5608); miR-656 (SEQ ID NO:5609); miR-658 (SEQ ID NO:5610); miR-660 (SEQ ID NO:5611); miR-664 (SEQ ID NO:5612); miR-664b (SEQ ID NO:5613); miR-665 (SEQ ID NO:5614); miR-669 (SEQ ID NO:5615); miR-670 (SEQ ID NO:5616); miR-671 (SEQ ID NO:5617); miR-677 (SEQ ID NO:5618); miR-708 (SEQ ID NO:5619); miR-744 (SEQ ID NO:5620); miR-758 (SEQ ID NO:5621); miR-759 (SEQ ID NO:5622); miR-760 (SEQ ID NO:5623); miR-761 (SEQ ID NO:5624); miR-763 (SEQ ID NO:5625); miR-764 (SEQ ID NO:5626); miR-767 (SEQ ID NO:5627); miR-769 (SEQ ID NO:5628); miR-873 (SEQ ID NO:5629); miR-874 (SEQ ID NO:5630); miR-875 (SEQ ID NO:5631); miR-876 (SEQ ID NO:5632); miR-877 (SEQ ID NO:5633); miR-885 (SEQ ID NO:5634); miR-935 (SEQ ID NO:5635); miR-940 (SEQ ID NO:5636); miR-1179 (SEQ ID NO:5637); miR-1185 (SEQ ID NO:5638); miR-1193 (SEQ ID NO:5639); miR-1197 (SEQ ID NO:5640); miR-1224 (SEQ ID NO:5641); miR-1225 (SEQ ID NO:5642); miR-1246 (SEQ ID NO:5643); miR-1247 (SEQ ID NO:5644); miR-1248-1 (SEQ ID NO:5645); miR-1248-2 (SEQ ID NO:5646); miR-1249 (SEQ ID NO:5647); miR-1251 (SEQ ID NO:5648); miR-1256 (SEQ ID NO:5649); miR-1260b (SEQ ID NO:5650); miR-1271 (SEQ ID NO:5651); miR-1277 (SEQ ID NO:5652); miR-1281 (SEQ ID NO:5653); miR-1282 (SEQ ID NO:5654); miR-1284 (SEQ ID NO:5655); miR-1287 (SEQ ID NO:5656); miR-1291 (SEQ ID NO:5657); miR-1296 (SEQ ID NO:5658); miR-1298 (SEQ ID NO:5659); miR-1301 (SEQ ID NO:5660); miR-1306 (SEQ ID NO:5661); miR-1307 (SEQ ID NO:5662); miR-1343 (SEQ ID NO:5663); miR-1388 (SEQ ID NO:5664); miR-1434 (SEQ ID NO:5665); miR-1468 (SEQ ID NO:5666); miR-1584 (SEQ ID NO:5667); miR-1603 (SEQ ID NO:5668); miR-1721 (SEQ ID NO:5669); miR-1777a (SEQ ID NO:5670); miR-1777b (SEQ ID NO:5671); miR-1814a (SEQ ID NO:5672); miR-1814b (SEQ ID NO:5673); miR-1814c (SEQ ID NO:5674); miR-1835 (SEQ ID NO:5675); miR-1839 (SEQ ID NO:5676); miR-1843 (SEQ ID NO:5677); miR-1940 (SEQ ID NO:5678); miR-2284a (SEQ ID NO:5679); miR-2284aa-1 (SEQ ID NO:5680); miR-2284aa-2 (SEQ ID NO:5681); miR-2284aa-3 (SEQ ID NO:5682); miR-2284aa-4 (SEQ ID NO:5683); miR-2284ab (SEQ ID NO:5684); miR-2284ac (SEQ ID NO:5685); miR-2284b (SEQ ID NO:5686); miR-2284c (SEQ ID NO:5687); miR-2284d (SEQ ID NO:5688); miR-2284e (SEQ ID NO:5689); miR-2284f (SEQ ID NO:5690); miR-2284g (SEQ ID NO:5691); miR-2284h (SEQ ID NO:5692); miR-2284i (SEQ ID NO:5693); miR-2284j (SEQ ID NO:5694); miR-2284k (SEQ ID NO:5695); miR-2284l (SEQ ID NO:5696); miR-2284m (SEQ ID NO:5697); miR-2284n (SEQ ID NO:5698); miR-2284o (SEQ ID NO:5699); miR-2284p (SEQ ID NO:5700); miR-2284q (SEQ ID NO:5701); miR-2284r (SEQ ID NO:5702); miR-2284s (SEQ ID NO:5703); miR-2284t (SEQ ID NO:5704); miR-2284u (SEQ ID NO:5705); miR-2284v (SEQ ID NO:5706); miR-2284w (SEQ ID NO:5707); miR-2284x (SEQ ID NO:5708); miR-2284y-1 (SEQ ID NO:5709); miR-2284y-2 (SEQ ID NO:5710); miR-2284y-3 (SEQ ID NO:5711); miR-2284y-4 (SEQ ID NO:5712); miR-2284y-5 (SEQ ID NO:5713); miR-2284y-6 (SEQ ID NO:5714); miR-2284y-7 (SEQ ID NO:5715); miR-2284z-1 (SEQ ID NO:5716); miR-2284z-2 (SEQ ID NO:5717); miR-2284z-3 (SEQ ID NO:5718); miR-2284z-4 (SEQ ID NO:5719); miR-2284z-5 (SEQ ID NO:5720); miR-2284z-6 (SEQ ID NO:5721); miR-2284z-7 (SEQ ID NO:5722); miR-2285a (SEQ ID NO:5723); miR-2285aa (SEQ ID NO:5724); miR-2285ab (SEQ ID NO:5725); miR-2285ac (SEQ ID NO:5726); miR-2285ad (SEQ ID NO:5727); miR-2285ae (SEQ ID NO:5728); miR-2285af-1 (SEQ ID NO:5729); miR-2285af-2 (SEQ ID NO:5730); miR-2285b-1 (SEQ ID NO:5731); miR-2285b-2 (SEQ ID NO:5732); miR-2285c (SEQ ID NO:5733); miR-2285d (SEQ ID NO:5734); miR-2285e-1 (SEQ ID NO:5735); miR-2285e-2 (SEQ ID NO:5736); miR-2285f-1 (SEQ ID NO:5737); miR-2285f-2 (SEQ ID NO:5738); miR-2285g-1 (SEQ ID NO:5739); miR-2285g-2 (SEQ ID NO:5740); miR-2285g-3 (SEQ ID NO:5741); miR-2285h (SEQ ID NO:5742); miR-2285i (SEQ ID NO:5743); miR-2285j-1 (SEQ ID NO:5744); miR-2285j-2 (SEQ ID NO:5745); miR-2285k-1 (SEQ ID NO:5746); miR-2285k-2 (SEQ ID NO:5747); miR-2285k-3 (SEQ ID NO:5748); miR-2285k-4 (SEQ ID NO:5749); miR-2285k-5 (SEQ ID NO:5750); miR-2285l (SEQ ID NO:5751); miR-2285m-1 (SEQ ID NO:5752); miR-2285m-2 (SEQ ID NO:5753); miR-2285m-3 (SEQ ID NO:5754); miR-2285m-4 (SEQ ID NO:5755); miR-2285m-5 (SEQ ID NO:5756); miR-2285n-1 (SEQ ID NO:5757); miR-2285n-2 (SEQ ID NO:5758); miR-2285n-3 (SEQ ID NO:5759); miR-2285n-4 (SEQ ID NO:5760); miR-2285n-5 (SEQ ID NO:5761); miR-2285n-6 (SEQ ID NO:5762); miR-2285n-7 (SEQ ID NO:5763); miR-2285o-1 (SEQ ID NO:5764); miR-2285o-2 (SEQ ID NO:5765); miR-2285o-3 (SEQ ID NO:5766); miR-2285o-4 (SEQ ID NO:5767); miR-2285o-5 (SEQ ID NO:5768); miR-2285p (SEQ ID NO:5769); miR-2285q (SEQ ID NO:5770); miR-2285r (SEQ ID NO:5771); miR-2285s (SEQ ID NO:5772); miR-2285t (SEQ ID NO:5773); miR-2285u (SEQ ID NO:5774); miR-2285v (SEQ ID NO:5775); miR-2285w (SEQ ID NO:5776); miR-2285x (SEQ ID NO:5777); miR-2285y (SEQ ID NO:5778); miR-2285z (SEQ ID NO:5779); miR-2286 (SEQ ID NO:5780); miR-2287 (SEQ ID NO:5781); miR-2288 (SEQ ID NO:5782); miR-2289 (SEQ ID NO:5783); miR-2290 (SEQ ID NO:5784); miR-2291 (SEQ ID NO:5785); miR-2292 (SEQ ID NO:5786); miR-2293 (SEQ ID NO:5787); miR-2294 (SEQ ID NO:5788); miR-2295 (SEQ ID NO:5789); miR-2296 (SEQ ID NO:5790); miR-2297 (SEQ ID NO:5791); miR-2298 (SEQ ID NO:5792); miR-2299 (SEQ ID NO:5793); miR-2300a (SEQ ID NO:5794); miR-2300b (SEQ ID NO:5795); miR-2301 (SEQ ID NO:5796); miR-2302 (SEQ ID NO:5797); miR-2303 (SEQ ID NO:5798); miR-2304 (SEQ ID NO:5799); miR-2305 (SEQ ID NO:5800); miR-2306 (SEQ ID NO:5801); miR-2307 (SEQ ID NO:5802); miR-2308 (SEQ ID NO:5803); miR-2309 (SEQ ID NO:5804); miR-2310 (SEQ ID NO:5805); miR-2311 (SEQ ID NO:5806); miR-2312 (SEQ ID NO:5807); miR-2313 (SEQ ID NO:5808); miR-2314 (SEQ ID NO:5809); miR-2315 (SEQ ID NO:5810); miR-2316 (SEQ ID NO:5811); miR-2317 (SEQ ID NO:5812); miR-2318 (SEQ ID NO:5813); miR-2319a (SEQ ID NO:5814); miR-2319b (SEQ ID NO:5815); miR-2320 (SEQ ID NO:5816); miR-2321 (SEQ ID NO:5817); miR-2322 (SEQ ID NO:5818); miR-2323 (SEQ ID NO:5819); miR-2324 (SEQ ID NO:5820); miR-2325a (SEQ ID NO:5821); miR-2325b (SEQ ID NO:5822); miR-2325c (SEQ ID NO:5823); miR-2326 (SEQ ID NO:5824); miR-2327 (SEQ ID NO:5825); miR-2328 (SEQ ID NO:5826); miR-2329-1 (SEQ ID NO:5827); miR-2329-2 (SEQ ID NO:5828); miR-2330 (SEQ ID NO:5829); miR-2331 (SEQ ID NO:5830); miR-2332 (SEQ ID NO:5831); miR-2333 (SEQ ID NO:5832); miR-2334 (SEQ ID NO:5833); miR-2335 (SEQ ID NO:5834); miR-2336 (SEQ ID NO:5835); miR-2337 (SEQ ID NO:5836); miR-2338 (SEQ ID NO:5837); miR-2339 (SEQ ID NO:5838); miR-2340 (SEQ ID NO:5839); miR-2341 (SEQ ID NO:5840); miR-2342 (SEQ ID NO:5841); miR-2343 (SEQ ID NO:5842); miR-2344 (SEQ ID NO:5843); miR-2345 (SEQ ID NO:5844); miR-2346 (SEQ ID NO:5845); miR-2347 (SEQ ID NO:5846); miR-2348 (SEQ ID NO:5847); miR-2349 (SEQ ID NO:5848); miR-2350 (SEQ ID NO:5849); miR-2351 (SEQ ID NO:5850); miR-2352 (SEQ ID NO:5851); miR-2353 (SEQ ID NO:5852); miR-2354 (SEQ ID NO:5853); miR-2355 (SEQ ID NO:5854); miR-2356 (SEQ ID NO:5855); miR-2357 (SEQ ID NO:5856); miR-2358 (SEQ ID NO:5857); miR-2359 (SEQ ID NO:5858); miR-2360 (SEQ ID NO:5859); miR-2361 (SEQ ID NO:5860); miR-2362 (SEQ ID NO:5861); miR-2363-1 (SEQ ID NO:5862); miR-2363-2 (SEQ ID NO:5863); miR-2364 (SEQ ID NO:5864); miR-2365 (SEQ ID NO:5865); miR-2366 (SEQ ID NO:5866); miR-2367 (SEQ ID NO:5867); miR-2368 (SEQ ID NO:5868); miR-2369 (SEQ ID NO:5869); miR-2370 (SEQ ID NO:5870); miR-2371 (SEQ ID NO:5871); miR-2372 (SEQ ID NO:5872); miR-2373 (SEQ ID NO:5873); miR-2374 (SEQ ID NO:5874); miR-2375 (SEQ ID NO:5875); miR-2376 (SEQ ID NO:5876); miR-2377 (SEQ ID NO:5877); miR-2378 (SEQ ID NO:5878); miR-2379 (SEQ ID NO:5879); miR-2380 (SEQ ID NO:5880); miR-2381 (SEQ ID NO:5881); miR-2382 (SEQ ID NO:5882); miR-2383 (SEQ ID NO:5883); miR-2384 (SEQ ID NO:5884); miR-2385 (SEQ ID NO:5885); miR-2386 (SEQ ID NO:5886); miR-2387 (SEQ ID NO:5887); miR-2388 (SEQ ID NO:5888); miR-2389 (SEQ ID NO:5889); miR-2390 (SEQ ID NO:5890); miR-2392 (SEQ ID NO:5891); miR-2393 (SEQ ID NO:5892); miR-2394 (SEQ ID NO:5893); miR-2395 (SEQ ID NO:5894); miR-2396 (SEQ ID NO:5895); miR-2397 (SEQ ID NO:5896); miR-2398 (SEQ ID NO:5897); miR-2399 (SEQ ID NO:5898); miR-2400 (SEQ ID NO:5899); miR-2401 (SEQ ID NO:5900); miR-2402 (SEQ ID NO:5901); miR-2403 (SEQ ID NO:5902); miR-2404-1 (SEQ ID NO:5903); miR-2404-2 (SEQ ID NO:5904); miR-2405 (SEQ ID NO:5905); miR-2406 (SEQ ID NO:5906); miR-2407 (SEQ ID NO:5907); miR-2408 (SEQ ID NO:5908); miR-2409 (SEQ ID NO:5909); miR-2410 (SEQ ID NO:5910); miR-2411 (SEQ ID NO:5911); miR-2412 (SEQ ID NO:5912); miR-2413 (SEQ ID NO:5913); miR-2414 (SEQ ID NO:5914); miR-2415 (SEQ ID NO:5915); miR-2416 (SEQ ID NO:5916); miR-2417 (SEQ ID NO:5917); miR-2418 (SEQ ID NO:5918); miR-2419 (SEQ ID NO:5919); miR-2420 (SEQ ID NO:5920); miR-2421 (SEQ ID NO:5921); miR-2422 (SEQ ID NO:5922); miR-2423 (SEQ ID NO:5923); miR-2424 (SEQ ID NO:5924); miR-2425 (SEQ ID NO:5925); miR-2426 (SEQ ID NO:5926); miR-2427 (SEQ ID NO:5927); miR-2428 (SEQ ID NO:5928); miR-2429 (SEQ ID NO:5929); miR-2430 (SEQ ID NO:5930); miR-2431 (SEQ ID NO:5931); miR-2432 (SEQ ID NO:5932); miR-2433 (SEQ ID NO:5933); miR-2434 (SEQ ID NO:5934); miR-2435 (SEQ ID NO:5935); miR-2436 (SEQ ID NO:5936); miR-2437 (SEQ ID NO:5937); miR-2438 (SEQ ID NO:5938); miR-2439 (SEQ ID NO:5939); miR-2440 (SEQ ID NO:5940); miR-2441 (SEQ ID NO:5941); miR-2442 (SEQ ID NO:5942); miR-2443 (SEQ ID NO:5943); miR-2444 (SEQ ID NO:5944); miR-2446 (SEQ ID NO:5945); miR-2447 (SEQ ID NO:5946); miR-2448 (SEQ ID NO:5947); miR-2449 (SEQ ID NO:5948); miR-2450a (SEQ ID NO:5949); miR-2450b (SEQ ID NO:5950); miR-2450c (SEQ ID NO:5951); miR-2451 (SEQ ID NO:5952); miR-2452 (SEQ ID NO:5953); miR-2453 (SEQ ID NO:5954); miR-2454 (SEQ ID NO:5955); miR-2455 (SEQ ID NO:5956); miR-2456 (SEQ ID NO:5957); miR-2457 (SEQ ID NO:5958); miR-2458 (SEQ ID NO:5959); miR-2459 (SEQ ID NO:5960); miR-2460 (SEQ ID NO:5961); miR-2461 (SEQ ID NO:5962); miR-2462 (SEQ ID NO:5963); miR-2463 (SEQ ID NO:5964); miR-2464 (SEQ ID NO:5965); miR-2465 (SEQ ID NO:5966); miR-2466 (SEQ ID NO:5967); miR-2467 (SEQ ID NO:5968); miR-2468 (SEQ ID NO:5969); miR-2469 (SEQ ID NO:5970); miR-2470 (SEQ ID NO:5971); miR-2471 (SEQ ID NO:5972); miR-2472 (SEQ ID NO:5973); miR-2473 (SEQ ID NO:5974); miR-2474 (SEQ ID NO:5975); miR-2475 (SEQ ID NO:5976); miR-2477 (SEQ ID NO:5977); miR-2478 (SEQ ID NO:5978); miR-2479 (SEQ ID NO:5979); miR-2480 (SEQ ID NO:5980); miR-2481 (SEQ ID NO:5981); miR-2482 (SEQ ID NO:5982); miR-2483 (SEQ ID NO:5983); miR-2484 (SEQ ID NO:5984); miR-2485 (SEQ ID NO:5985); miR-2486 (SEQ ID NO:5986); miR-2487 (SEQ ID NO:5987); miR-2488 (SEQ ID NO:5988); miR-2489 (SEQ ID NO:5989); miR-2881 (SEQ ID NO:5990); miR-2882 (SEQ ID NO:5991); miR-2883 (SEQ ID NO:5992); miR-2885 (SEQ ID NO:5993); miR-2886 (SEQ ID NO:5994); miR-2887-1 (SEQ ID NO:5995); miR-2887-2 (SEQ ID NO:5996); miR-2888-1 (SEQ ID NO:5997); miR-2888-2 (SEQ ID NO:5998); miR-2889 (SEQ ID NO:5999); miR-2890 (SEQ ID NO:6000); miR-2891 (SEQ ID NO:6001); miR-2892 (SEQ ID NO:6002); miR-2893 (SEQ ID NO:6003); miR-2894 (SEQ ID NO:6004); miR-2895 (SEQ ID NO:6005); miR-2896 (SEQ ID NO:6006); miR-2897 (SEQ ID NO:6007); miR-2898 (SEQ ID NO:6008); miR-2899 (SEQ ID NO:6009); miR-2900 (SEQ ID NO:6010); miR-2901 (SEQ ID NO:6011); miR-2902 (SEQ ID NO:6012); miR-2903 (SEQ ID NO:6013); miR-2904-1 (SEQ ID NO:6014); miR-2904-2 (SEQ ID NO:6015); miR-2904-3 (SEQ ID NO:6016); miR-2917 (SEQ ID NO:6017); miR-2957 (SEQ ID NO:6018); miR-3120 (SEQ ID NO:6019); miR-3141 (SEQ ID NO:6020); miR-3154 (SEQ ID NO:6021); miR-3431 (SEQ ID NO:6022); miR-3432-1 (SEQ ID NO:6023); miR-3432-2 (SEQ ID NO:6024); miR-3578 (SEQ ID NO:6025); miR-3596 (SEQ ID NO:6026); miR-3600 (SEQ ID NO:6027); miR-3601 (SEQ ID NO:6028); miR-3602 (SEQ ID NO:6029); miR-3604-1 (SEQ ID NO:6030); miR-3604-2 (SEQ ID NO:6031); miR-3613 (SEQ ID NO:6032); miR-3613b (SEQ ID NO:6033); miR-3660 (SEQ ID NO:6034); miR-3956 (SEQ ID NO:6035); miR-3957 (SEQ ID NO:6036); miR-4286-1 (SEQ ID NO:6037); miR-4286-2 (SEQ ID NO:6038); miR-6119 (SEQ ID NO:6039); miR-6120 (SEQ ID NO:6040); miR-6121 (SEQ ID NO:6041); miR-6122 (SEQ ID NO:6042); miR-6123 (SEQ ID NO:6043); miR-6516 (SEQ ID NO:6044); miR-6517 (SEQ ID NO:6045); miR-6518 (SEQ ID NO:6046); miR-6519 (SEQ ID NO:6047); miR-6520 (SEQ ID NO:6048); miR-6521 (SEQ ID NO:6049); miR-6522 (SEQ ID NO:6050); miR-6523 (SEQ ID NO:6051); miR-6523b (SEQ ID NO:6052); miR-6524 (SEQ ID NO:6053); miR-6525 (SEQ ID NO:6054); miR-6526-1 (SEQ ID NO:6055); miR-6526-2 (SEQ ID NO:6056); miR-6526-3 (SEQ ID NO:6057); miR-6527 (SEQ ID NO:6058); miR-6528 (SEQ ID NO:6059); miR-6529 (SEQ ID NO:6060); miR-6529b (SEQ ID NO:6061); miR-6530 (SEQ ID NO:6062); miR-6531 (SEQ ID NO:6063); miR-6532 (SEQ ID NO:6064); miR-6533 (SEQ ID NO:6065); miR-6534 (SEQ ID NO:6066); miR-6535 (SEQ ID NO:6067); miR-6536-1 (SEQ ID NO:6068); miR-6536-2 (SEQ ID NO:6069); miR-7691 (SEQ ID NO:6070); miR-7857 (SEQ ID NO:6071); miR-7858 (SEQ ID NO:6072); miR-7859 (SEQ ID NO:6073); miR-7860 (SEQ ID NO:6074); miR-7861 (SEQ ID NO:6075); miR-7862 (SEQ ID NO:6076); miR-7863 (SEQ ID NO:6077); miR-7864 (SEQ ID NO:6078); and miR-7865 (SEQ ID NO:6079).

The following sheep miRNAs could be used: let-7a (SEQ ID NO:6080); let-7b (SEQ ID NO:6081); let-7c (SEQ ID NO:6082); let-7d (SEQ ID NO:6083); let-7f (SEQ ID NO:6084); let-7g (SEQ ID NO:6085); let-7i (SEQ ID NO:6086); miR-10a (SEQ ID NO:6087); miR-10b (SEQ ID NO:6088); miR-16b (SEQ ID NO:6089); miR-17 (SEQ ID NO:6090); miR-19b (SEQ ID NO:6091); miR-21 (SEQ ID NO:6092); miR-22 (SEQ ID NO:6093); miR-23a (SEQ ID NO:6094); miR-23b (SEQ ID NO:6095); miR-25 (SEQ ID NO:6096); miR-26a (SEQ ID NO:6097); miR-26b (SEQ ID NO:6098); miR-27a (SEQ ID NO:6099); miR-29a (SEQ ID NO:6100); miR-29b (SEQ ID NO:6101); miR-30a (SEQ ID NO:6102); miR-30b (SEQ ID NO:6103); miR-30c (SEQ ID NO:6104); miR-30d (SEQ ID NO:6105); miR-99a (SEQ ID NO:6106); miR-103 (SEQ ID NO:6107); miR-106a (SEQ ID NO:6108); miR-106b (SEQ ID NO:6109); miR-107 (SEQ ID NO:6110); miR-125b (SEQ ID NO:6111); miR-127 (SEQ ID NO:6112); miR-133 (SEQ ID NO:6113); miR-134 (SEQ ID NO:6114); miR-136 (SEQ ID NO:6115); miR-143 (SEQ ID NO:6116); miR-148a (SEQ ID NO:6117); miR-150 (SEQ ID NO:6118); miR-152 (SEQ ID NO:6119); miR-154a (SEQ ID NO:6120); miR-154b (SEQ ID NO:6121); miR-181a-1 (SEQ ID NO:6122); miR-181a-2 (SEQ ID NO:6123); miR-191 (SEQ ID NO:6124); miR-194 (SEQ ID NO:6125); miR-199a (SEQ ID NO:6126); miR-200a (SEQ ID NO:6127); miR-200b (SEQ ID NO:6128); miR-200c (SEQ ID NO:6129); miR-218a (SEQ ID NO:6130); miR-221 (SEQ ID NO:6131); miR-299 (SEQ ID NO:6132); miR-323a (SEQ ID NO:6133); miR-323b (SEQ ID NO:6134); miR-323c (SEQ ID NO:6135); miR-329a (SEQ ID NO:6136); miR-329b (SEQ ID NO:6137); miR-362 (SEQ ID NO:6138); miR-369 (SEQ ID NO:6139); miR-370 (SEQ ID NO:6140); miR-374a (SEQ ID NO:6141); miR-374b (SEQ ID NO:6142); miR-376a (SEQ ID NO:6143); miR-376b (SEQ ID NO:6144); miR-376c (SEQ ID NO:6145); miR-376d (SEQ ID NO:6146); miR-376e (SEQ ID NO:6147); miR-377 (SEQ ID NO:6148); miR-379 (SEQ ID NO:6149); miR-380 (SEQ ID NO:6150); miR-381 (SEQ ID NO:6151); miR-382 (SEQ ID NO:6152); miR-409 (SEQ ID NO:6153); miR-410 (SEQ ID NO:6154); miR-411a (SEQ ID NO:6155); miR-411b (SEQ ID NO:6156); miR-412 (SEQ ID NO:6157); miR-431 (SEQ ID NO:6158); miR-432 (SEQ ID NO:6159); miR-433 (SEQ ID NO:6160); miR-485 (SEQ ID NO:6161); miR-487a (SEQ ID NO:6162); miR-487b (SEQ ID NO:6163); miR-493 (SEQ ID NO:6164); miR-494 (SEQ ID NO:6165); miR-495 (SEQ ID NO:6166); miR-496 (SEQ ID NO:6167); miR-539 (SEQ ID NO:6168); miR-541 (SEQ ID NO:6169); miR-543 (SEQ ID NO:6170); miR-544 (SEQ ID NO:6171); miR-654 (SEQ ID NO:6172); miR-655 (SEQ ID NO:6173); miR-665 (SEQ ID NO:6174); miR-668 (SEQ ID NO:6175); miR-758 (SEQ ID NO:6176); miR-1185 (SEQ ID NO:6177); miR-1193 (SEQ ID NO:6178); miR-1197 (SEQ ID NO:6179); miR-3955 (SEQ ID NO:6180); miR-3956 (SEQ ID NO:6181); miR-3957 (SEQ ID NO:6182); miR-3958 (SEQ ID NO:6183); and miR-3959 (SEQ ID NO:6184).

The following pig miRNAs could be used: let-7a-1 (SEQ ID NO:6185); let-7a-2 (SEQ ID NO:6186); let-7c (SEQ ID NO:6187); let-7d (SEQ ID NO:6188); let-7e (SEQ ID NO:6189); let-7f-1 (SEQ ID NO:6190); let-7f-2 (SEQ ID NO:6191); let-7g (SEQ ID NO:6192); let-7i (SEQ ID NO:6193); miR-1 (SEQ ID NO:6194); miR-7-1 (SEQ ID NO:6195); miR-7-2 (SEQ ID NO:6196); miR-9-1 (SEQ ID NO:6197); miR-9-2 (SEQ ID NO:6198); miR-9-3 (SEQ ID NO:6199); miR-10a (SEQ ID NO:6200); miR-10b (SEQ ID NO:6201); miR-15a (SEQ ID NO:6202); miR-15b (SEQ ID NO:6203); miR-16-1 (SEQ ID NO:6204); miR-16-2 (SEQ ID NO:6205); miR-17 (SEQ ID NO:6206); miR-18a (SEQ ID NO:6207); miR-18b (SEQ ID NO:6208); miR-19a (SEQ ID NO:6209); miR-19b-1 (SEQ ID NO:6210); miR-19b-2 (SEQ ID NO:6211); miR-20a (SEQ ID NO:6212); miR-20b-1 (SEQ ID NO:6213); miR-20b-2 (SEQ ID NO:6214); miR-21 (SEQ ID NO:6215); miR-22 (SEQ ID NO:6216); miR-23a (SEQ ID NO:6217); miR-23b (SEQ ID NO:6218); miR-24-1 (SEQ ID NO:6219); miR-24-2 (SEQ ID NO:6220); miR-26a (SEQ ID NO:6221); miR-27a (SEQ ID NO:6222); miR-27b (SEQ ID NO:6223); miR-28 (SEQ ID NO:6224); miR-29a (SEQ ID NO:6225); miR-29b-1 (SEQ ID NO:6226); miR-29b-2 (SEQ ID NO:6227); miR-29c (SEQ ID NO:6228); miR-30a (SEQ ID NO:6229); miR-30b (SEQ ID NO:6230); miR-30c-1 (SEQ ID NO:6231); miR-30c-2 (SEQ ID NO:6232); miR-30d (SEQ ID NO:6233); miR-30e (SEQ ID NO:6234); miR-31 (SEQ ID NO:6235); miR-32 (SEQ ID NO:6236); miR-34a (SEQ ID NO:6237); miR-34c-1 (SEQ ID NO:6238); miR-34c-2 (SEQ ID NO:6239); miR-92a-1 (SEQ ID NO:6240); miR-92a-2 (SEQ ID NO:6241); miR-92b (SEQ ID NO:6242); miR-95 (SEQ ID NO:6243); miR-98 (SEQ ID NO:6244); miR-99a (SEQ ID NO:6245); miR-99b (SEQ ID NO:6246); miR-100 (SEQ ID NO:6247); miR-101-1 (SEQ ID NO:6248); miR-101-2 (SEQ ID NO:6249); miR-103-1 (SEQ ID NO:6250); miR-103-2 (SEQ ID NO:6251); miR-105-1 (SEQ ID NO:6252); miR-105-2 (SEQ ID NO:6253); miR-106a (SEQ ID NO:6254); miR-107 (SEQ ID NO:6255); miR-122 (SEQ ID NO:6256); miR-124a-1 (SEQ ID NO:6257); miR-124a-2 (SEQ ID NO:6258); miR-125a (SEQ ID NO:6259); miR-125b-1 (SEQ ID NO:6260); miR-125b-2 (SEQ ID NO:6261); miR-126 (SEQ ID NO:6262); miR-127 (SEQ ID NO:6263); miR-128-1 (SEQ ID NO:6264); miR-128-2 (SEQ ID NO:6265); miR-129a (SEQ ID NO:6266); miR-129b (SEQ ID NO:6267); miR-130a (SEQ ID NO:6268); miR-130b (SEQ ID NO:6269); miR-132 (SEQ ID NO:6270); miR-133a-1 (SEQ ID NO:6271); miR-133a-2 (SEQ ID NO:6272); miR-133b (SEQ ID NO:6273); miR-135-1 (SEQ ID NO:6274); miR-135-2 (SEQ ID NO:6275); miR-136 (SEQ ID NO:6276); miR-137 (SEQ ID NO:6277); miR-138 (SEQ ID NO:6278); miR-139 (SEQ ID NO:6279); miR-140 (SEQ ID NO:6280); miR-142 (SEQ ID NO:6281); miR-143 (SEQ ID NO:6282); miR-144 (SEQ ID NO:6283); miR-145 (SEQ ID NO:6284); miR-146a (SEQ ID NO:6285); miR-146b (SEQ ID NO:6286); miR-148a (SEQ ID NO:6287); miR-148b (SEQ ID NO:6288); miR-149 (SEQ ID NO:6289); miR-150-1 (SEQ ID NO:6290); miR-150-2 (SEQ ID NO:6291); miR-151 (SEQ ID NO:6292); miR-152 (SEQ ID NO:6293); miR-153 (SEQ ID NO:6294); miR-155 (SEQ ID NO:6295); miR-181a-1 (SEQ ID NO:6296); miR-181a-2 (SEQ ID NO:6297); miR-181b-1 (SEQ ID NO:6298); miR-181b-2 (SEQ ID NO:6299); miR-181c (SEQ ID NO:6300); miR-181d (SEQ ID NO:6301); miR-182 (SEQ ID NO:6302); miR-183 (SEQ ID NO:6303); miR-184 (SEQ ID NO:6304); miR-185 (SEQ ID NO:6305); miR-186 (SEQ ID NO:6306); miR-187 (SEQ ID NO:6307); miR-190a (SEQ ID NO:6308); miR-190b (SEQ ID NO:6309); miR-191 (SEQ ID NO:6310); miR-192 (SEQ ID NO:6311); miR-193a (SEQ ID NO:6312); miR-194a (SEQ ID NO:6313); miR-194b (SEQ ID NO:6314); miR-195 (SEQ ID NO:6315); miR-196a-1 (SEQ ID NO:6316); miR-196a-2 (SEQ ID NO:6317); miR-196b-1 (SEQ ID NO:6318); miR-196b-2 (SEQ ID NO:6319); miR-199a-1 (SEQ ID NO:6320); miR-199a-2 (SEQ ID NO:6321); miR-199b (SEQ ID NO:6322); miR-202 (SEQ ID NO:6323); miR-204 (SEQ ID NO:6324); miR-205 (SEQ ID NO:6325); miR-206 (SEQ ID NO:6326); miR-208b (SEQ ID NO:6327); miR-210 (SEQ ID NO:6328); miR-212 (SEQ ID NO:6329); miR-214 (SEQ ID NO:6330); miR-215 (SEQ ID NO:6331); miR-216-1 (SEQ ID NO:6332); miR-216-2 (SEQ ID NO:6333); miR-217-1 (SEQ ID NO:6334); miR-217-2 (SEQ ID NO:6335); miR-218-1 (SEQ ID NO:6336); miR-218-2 (SEQ ID NO:6337); miR-218b (SEQ ID NO:6338); miR-219 (SEQ ID NO:6339); miR-221 (SEQ ID NO:6340); miR-222 (SEQ ID NO:6341); miR-224 (SEQ ID NO:6342); miR-296 (SEQ ID NO:6343); miR-299 (SEQ ID NO:6344); miR-301 (SEQ ID NO:6345); miR-320 (SEQ ID NO:6346); miR-323 (SEQ ID NO:6347); miR-324 (SEQ ID NO:6348); miR-325 (SEQ ID NO:6349); miR-326 (SEQ ID NO:6350); miR-328 (SEQ ID NO:6351); miR-331 (SEQ ID NO:6352); miR-335 (SEQ ID NO:6353); miR-338 (SEQ ID NO:6354); miR-339-1 (SEQ ID NO:6355); miR-339-2 (SEQ ID NO:6356); miR-340-1 (SEQ ID NO:6357); miR-340-2 (SEQ ID NO:6358); miR-342 (SEQ ID NO:6359); miR-345-1 (SEQ ID NO:6360); miR-345-2 (SEQ ID NO:6361); miR-361 (SEQ ID NO:6362); miR-362 (SEQ ID NO:6363); miR-363-1 (SEQ ID NO:6364); miR-363-2 (SEQ ID NO:6365); miR-365-1 (SEQ ID NO:6366); miR-365-2 (SEQ ID NO:6367); miR-369 (SEQ ID NO:6368); miR-370 (SEQ ID NO:6369); miR-374a (SEQ ID NO:6370); miR-374b (SEQ ID NO:6371); miR-376a (SEQ ID NO:6372); miR-376b (SEQ ID NO:6373); miR-376c (SEQ ID NO:6374); miR-378-1 (SEQ ID NO:6375); miR-378-2 (SEQ ID NO:6376); miR-381 (SEQ ID NO:6377); miR-382 (SEQ ID NO:6378); miR-383 (SEQ ID NO:6379); miR-411 (SEQ ID NO:6380); miR-421 (SEQ ID NO:6381); miR-423 (SEQ ID NO:6382); miR-424 (SEQ ID NO:6383); miR-425 (SEQ ID NO:6384); miR-429 (SEQ ID NO:6385); miR-432 (SEQ ID NO:6386); miR-450a (SEQ ID NO:6387); miR-450b (SEQ ID NO:6388); miR-450c (SEQ ID NO:6389); miR-451 (SEQ ID NO:6390); miR-452 (SEQ ID NO:6391); miR-455 (SEQ ID NO:6392); miR-484 (SEQ ID NO:6393); miR-486-1 (SEQ ID NO:6394); miR-486-2 (SEQ ID NO:6395); miR-487b (SEQ ID NO:6396); miR-489 (SEQ ID NO:6397); miR-490-1 (SEQ ID NO:6398); miR-490-2 (SEQ ID NO:6399); miR-491 (SEQ ID NO:6400); miR-493 (SEQ ID NO:6401); miR-494 (SEQ ID NO:6402); miR-497 (SEQ ID NO:6403); miR-499 (SEQ ID NO:6404); miR-500 (SEQ ID NO:6405); miR-503 (SEQ ID NO:6406); miR-504 (SEQ ID NO:6407); miR-505 (SEQ ID NO:6408); miR-532 (SEQ ID NO:6409); miR-542 (SEQ ID NO:6410); miR-545 (SEQ ID NO:6411); miR-551a (SEQ ID NO:6412); miR-574 (SEQ ID NO:6413); miR-582 (SEQ ID NO:6414); miR-615 (SEQ ID NO:6415); miR-628 (SEQ ID NO:6416); miR-652 (SEQ ID NO:6417); miR-664 (SEQ ID NO:6418); miR-671 (SEQ ID NO:6419); miR-676-1 (SEQ ID NO:6420); miR-676-2 (SEQ ID NO:6421); miR-708 (SEQ ID NO:6422); miR-744 (SEQ ID NO:6423); miR-758 (SEQ ID NO:6424); miR-769 (SEQ ID NO:6425); miR-874 (SEQ ID NO:6426); miR-885 (SEQ ID NO:6427); miR-935 (SEQ ID NO:6428); miR-1224 (SEQ ID NO:6429); miR-1249-1 (SEQ ID NO:6430); miR-1249-2 (SEQ ID NO:6431); miR-1271 (SEQ ID NO:6432); miR-1277 (SEQ ID NO:6433); miR-1285 (SEQ ID NO:6434); miR-1296 (SEQ ID NO:6435); miR-1306 (SEQ ID NO:6436); miR-1307 (SEQ ID NO:6437); miR-1343 (SEQ ID NO:6438); miR-1468 (SEQ ID NO:6439); miR-1839 (SEQ ID NO:6440); miR-2320 (SEQ ID NO:6441); miR-2366-1 (SEQ ID NO:6442); miR-2366-2 (SEQ ID NO:6443); miR-2411 (SEQ ID NO:6444); miR-2483 (SEQ ID NO:6445); miR-3613 (SEQ ID NO:6446); miR-4331 (SEQ ID NO:6447); miR-4332 (SEQ ID NO:6448); miR-4334 (SEQ ID NO:6449); miR-4335 (SEQ ID NO:6450); miR-4337 (SEQ ID NO:6451); miR-4338 (SEQ ID NO:6452); miR-4339 (SEQ ID NO:6453); miR-7134 (SEQ ID NO:6454); miR-7135 (SEQ ID NO:6455); miR-7136 (SEQ ID NO:6456); miR-7137 (SEQ ID NO:6457); miR-7138 (SEQ ID NO:6458); miR-7139 (SEQ ID NO:6459); miR-7140 (SEQ ID NO:6460); miR-7141 (SEQ ID NO:6461); miR-7142 (SEQ ID NO:6462); miR-7143 (SEQ ID NO:6463); and miR-7144 (SEQ ID NO:6464).

The following rice miRNAs can be used: MIR156a (SEQ ID NO:6465); MIR156b (SEQ ID NO:6466); MIR156c (SEQ ID NO:6467); MIR156d (SEQ ID NO:6468); MIR156e (SEQ ID NO:6469); MIR156f (SEQ ID NO:6470); MIR156g (SEQ ID NO:6471); MIR156h (SEQ ID NO:6472); MIR156i (SEQ ID NO:6473); MIR156j (SEQ ID NO:6474); MIR156k (SEQ ID NO:6475); MIR156l (SEQ ID NO:6476); MIR159a (SEQ ID NO:6477); MIR159b (SEQ ID NO:6478); MIR159c (SEQ ID NO:6479); MIR159d (SEQ ID NO:6480); MIR159e (SEQ ID NO:6481); MIR159f (SEQ ID NO:6482); MIR160a (SEQ ID NO:6483); MIR160b (SEQ ID NO:6484); MIR160c (SEQ ID NO:6485); MIR160d (SEQ ID NO:6486); MIR160e (SEQ ID NO:6487); MIR160f (SEQ ID NO:6488); MIR162a (SEQ ID NO:6489); MIR162b (SEQ ID NO:6490); MIR164a (SEQ ID NO:6491); MIR164b (SEQ ID NO:6492); MIR164c (SEQ ID NO:6493); MIR164d (SEQ ID NO:6494); MIR164e (SEQ ID NO:6495); MIR164f (SEQ ID NO:6496); MIR166a (SEQ ID NO:6497); MIR166b (SEQ ID NO:6498); MIR166c (SEQ ID NO:6499); MIR166d (SEQ ID NO:6500); MIR166e (SEQ ID NO:6501); MIR166f (SEQ ID NO:6502); MIR166g (SEQ ID NO:6503); MIR166h (SEQ ID NO:6504); MIR166i (SEQ ID NO:6505); MIR166j (SEQ ID NO:6506); MIR166k (SEQ ID NO:6507); MIR166l (SEQ ID NO:6508); MIR166m (SEQ ID NO:6509); MIR167a (SEQ ID NO:6510); MIR167b (SEQ ID NO:6511); MIR167c (SEQ ID NO:6512); MIR167d (SEQ ID NO:6513); MIR167e (SEQ ID NO:6514); MIR167f (SEQ ID NO:6515); MIR167g (SEQ ID NO:6516); MIR167h (SEQ ID NO:6517); MIR167i (SEQ ID NO:6518); MIR167j (SEQ ID NO:6519); MIR168a (SEQ ID NO:6520); MIR168b (SEQ ID NO:6521); MIR169a (SEQ ID NO:6522); MIR169b (SEQ ID NO:6523); MIR169c (SEQ ID NO:6524); MIR169d (SEQ ID NO:6525); MIR169e (SEQ ID NO:6526); MIR169f (SEQ ID NO:6527); MIR169g (SEQ ID NO:6528); MIR169h (SEQ ID NO:6529); MIR169i (SEQ ID NO:6530); MIR169j (SEQ ID NO:6531); MIR169k (SEQ ID NO:6532); MIR169l (SEQ ID NO:6533); MIR169m (SEQ ID NO:6534); MIR169n (SEQ ID NO:6535); MIR1690 (SEQ ID NO:6536); MIR169p (SEQ ID NO:6537); MIR169q (SEQ ID NO:6538); MIR169r (SEQ ID NO:6539); MIR171a (SEQ ID NO:6540); MIR171b (SEQ ID NO:6541); MIR171c (SEQ ID NO:6542); MIR171d (SEQ ID NO:6543); MIR171e (SEQ ID NO:6544); MIR171f (SEQ ID NO:6545); MIR171g (SEQ ID NO:6546); MIR171h (SEQ ID NO:6547); MIR171i (SEQ ID NO:6548); MIR172a (SEQ ID NO:6549); MIR172b (SEQ ID NO:6550); MIR172c (SEQ ID NO:6551); MIR172d (SEQ ID NO:6552); MIR319a (SEQ ID NO:6553); MIR319b (SEQ ID NO:6554); MIR390 (SEQ ID NO:6555); MIR393a (SEQ ID NO:6556); MIR393b (SEQ ID NO:6557); MIR394 (SEQ ID NO:6558); MIR395a (SEQ ID NO:6559); MIR395b (SEQ ID NO:6560); MIR395c (SEQ ID NO:6561); MIR395d (SEQ ID NO:6562); MIR395e (SEQ ID NO:6563); MIR395f (SEQ ID NO:6564); MIR395g (SEQ ID NO:6565); MIR395h (SEQ ID NO:6566); MIR395i (SEQ ID NO:6567); MIR395j (SEQ ID NO:6568); MIR395k (SEQ ID NO:6569); MIR395l (SEQ ID NO:6570); MIR395m (SEQ ID NO:6571); MIR395n (SEQ ID NO:6572); MIR395o (SEQ ID NO:6573); MIR395p (SEQ ID NO:6574); MIR395q (SEQ ID NO:6575); MIR395r (SEQ ID NO:6576); MIR395s (SEQ ID NO:6577); MIR395t (SEQ ID NO:6578); MIR395u (SEQ ID NO:6579); MIR395v (SEQ ID NO:6580); MIR395w (SEQ ID NO:6581); MIR395x (SEQ ID NO:6582); MIR395y (SEQ ID NO:6583); MIR396a (SEQ ID NO:6584); MIR396b (SEQ ID NO:6585); MIR396c (SEQ ID NO:6586); MIR396d (SEQ ID NO:6587); MIR396e (SEQ ID NO:6588); MIR396f (SEQ ID NO:6589); MIR396g (SEQ ID NO:6590); MIR396h (SEQ ID NO:6591); MIR397a (SEQ ID NO:6592); MIR397b (SEQ ID NO:6593); MIR398a (SEQ ID NO:6594); MIR398b (SEQ ID NO:6595); MIR399a (SEQ ID NO:6596); MIR399b (SEQ ID NO:6597); MIR399c (SEQ ID NO:6598); MIR399d (SEQ ID NO:6599); MIR399e (SEQ ID NO:6600); MIR399f (SEQ ID NO:6601); MIR399g (SEQ ID NO:6602); MIR399h (SEQ ID NO:6603); MIR399i (SEQ ID NO:6604); MIR399j (SEQ ID NO:6605); MIR399k (SEQ ID NO:6606); MIR408 (SEQ ID NO:6607); MIR413 (SEQ ID NO:6608); MIR414 (SEQ ID NO:6609); MIR415 (SEQ ID NO:6610); MIR416 (SEQ ID NO:6611); MIR417 (SEQ ID NO:6612); MIR418 (SEQ ID NO:6613); MIR419 (SEQ ID NO:6614); MIR426 (SEQ ID NO:6615); MIR435 (SEQ ID NO:6616); MIR437 (SEQ ID NO:6617); MIR438 (SEQ ID NO:6618); MIR439a (SEQ ID NO:6619); MIR439b (SEQ ID NO:6620); MIR439c (SEQ ID NO:6621); MIR439d (SEQ ID NO:6622); MIR439e (SEQ ID NO:6623); MIR439f (SEQ ID NO:6624); MIR439g (SEQ ID NO:6625); MIR439h (SEQ ID NO:6626); MIR439i (SEQ ID NO:6627); MIR440 (SEQ ID NO:6628); MIR443 (SEQ ID NO:6629); MIR444a (SEQ ID NO:6630); MIR444b (SEQ ID NO:6631); MIR444c (SEQ ID NO:6632); MIR444d (SEQ ID NO:6633); MIR444e (SEQ ID NO:6634); MIR444f (SEQ ID NO:6635); MIR528 (SEQ ID NO:6636); MIR529a (SEQ ID NO:6637); MIR529b (SEQ ID NO:6638); MIR530 (SEQ ID NO:6639); MIR531a (SEQ ID NO:6640); MIR531b (SEQ ID NO:6641); MIR531c (SEQ ID NO:6642); MIR535 (SEQ ID NO:6643); MIR810a (SEQ ID NO:6644); MIR810b (SEQ ID NO:6645); MIR812a (SEQ ID NO:6646); MIR812b (SEQ ID NO:6647); MIR812c (SEQ ID NO:6648); MIR812d (SEQ ID NO:6649); MIR812e (SEQ ID NO:6650); MIR812f (SEQ ID NO:6651); MIR812g (SEQ ID NO:6652); MIR812h (SEQ ID NO:6653); MIR812i (SEQ ID NO:6654); MIR812j (SEQ ID NO:6655); MIR812k (SEQ ID NO:6656); MIR812l (SEQ ID NO:6657); MIR812m (SEQ ID NO:6658); MIR812n (SEQ ID NO:6659); MIR812o (SEQ ID NO:6660); MIR812p (SEQ ID NO:6661); MIR812q (SEQ ID NO:6662); MIR812r (SEQ ID NO:6663); MIR812s (SEQ ID NO:6664); MIR812t (SEQ ID NO:6665); MIR812u (SEQ ID NO:6666); MIR812v (SEQ ID NO:6667); MIR814a (SEQ ID NO:6668); MIR814b (SEQ ID NO:6669); MIR814c (SEQ ID NO:6670); MIR815a (SEQ ID NO:6671); MIR815b (SEQ ID NO:6672); MIR815c (SEQ ID NO:6673); MIR816 (SEQ ID NO:6674); MIR817 (SEQ ID NO:6675); MIR818a (SEQ ID NO:6676); MIR818b (SEQ ID NO:6677); MIR818c (SEQ ID NO:6678); MIR818d (SEQ ID NO:6679); MIR818e (SEQ ID NO:6680); MIR818f (SEQ ID NO:6681); MIR820a (SEQ ID NO:6682); MIR820b (SEQ ID NO:6683); MIR820c (SEQ ID NO:6684); MIR821a (SEQ ID NO:6685); MIR821b (SEQ ID NO:6686); MIR821c (SEQ ID NO:6687); MIR827 (SEQ ID NO:6688); MIR1319a (SEQ ID NO:6689); MIR1319b (SEQ ID NO:6690); MIR1320 (SEQ ID NO:6691); MIR1423 (SEQ ID NO:6692); MIR1424 (SEQ ID NO:6693); MIR1425 (SEQ ID NO:6694); MIR1426 (SEQ ID NO:6695); MIR1427 (SEQ ID NO:6696); MIR1428a (SEQ ID NO:6697); MIR1428b (SEQ ID NO:6698); MIR1428c (SEQ ID NO:6699); MIR1428d (SEQ ID NO:6700); MIR1428e (SEQ ID NO:6701); MIR1428f (SEQ ID NO:6702); MIR1428g (SEQ ID NO:6703); MIR1429 (SEQ ID NO:6704); MIR1430 (SEQ ID NO:6705); MIR1431 (SEQ ID NO:6706); MIR1432 (SEQ ID NO:6707); MIR1435 (SEQ ID NO:6708); MIR1436 (SEQ ID NO:6709); MIR1437 (SEQ ID NO:6710); MIR1437b (SEQ ID NO:6711); MIR1438 (SEQ ID NO:6712); MIR1439 (SEQ ID NO:6713); MIR1440a (SEQ ID NO:6714); MIR1440b (SEQ ID NO:6715); MIR1441 (SEQ ID NO:6716); MIR1442 (SEQ ID NO:6717); MIR1846a (SEQ ID NO:6718); MIR1846b (SEQ ID NO:6719); MIR1846c (SEQ ID NO:6720); MIR1846d (SEQ ID NO:6721); MIR1846e (SEQ ID NO:6722); MIR1847 (SEQ ID NO:6723); MIR1848 (SEQ ID NO:6724); MIR1849 (SEQ ID NO:6725); MIR1850 (SEQ ID NO:6726); MIR1851 (SEQ ID NO:6727); MIR1852 (SEQ ID NO:6728); MIR1853 (SEQ ID NO:6729); MIR1854 (SEQ ID NO:6730); MIR1855 (SEQ ID NO:6731); MIR1856 (SEQ ID NO:6732); MIR1857 (SEQ ID NO:6733); MIR1858a (SEQ ID NO:6734); MIR1858b (SEQ ID NO:6735); MIR1859 (SEQ ID NO:6736); MIR1860 (SEQ ID NO:6737); MIR1861a (SEQ ID NO:6738); MIR1861b (SEQ ID NO:6739); MIR1861c (SEQ ID NO:6740); MIR1861d (SEQ ID NO:6741); MIR1861e (SEQ ID NO:6742); MIR1861f (SEQ ID NO:6743); MIR1861g (SEQ ID NO:6744); MIR1861h (SEQ ID NO:6745); MIR1861i (SEQ ID NO:6746); MIR1861j (SEQ ID NO:6747); MIR1861k (SEQ ID NO:6748); MIR1861l (SEQ ID NO:6749); MIR1861m (SEQ ID NO:6750); MIR1861n (SEQ ID NO:6751); MIR1861o (SEQ ID NO:6752); MIR1862a (SEQ ID NO:6753); MIR1862b (SEQ ID NO:6754); MIR1862c (SEQ ID NO:6755); MIR1862d (SEQ ID NO:6756); MIR1862e (SEQ ID NO:6757); MIR1862f (SEQ ID NO:6758); MIR1862g (SEQ ID NO:6759); MIR1863a (SEQ ID NO:6760); MIR1863b (SEQ ID NO:6761); MIR1863c (SEQ ID NO:6762); MIR1864 (SEQ ID NO:6763); MIR1865 (SEQ ID NO:6764); MIR1866 (SEQ ID NO:6765); MIR1868 (SEQ ID NO:6766); MIR1869 (SEQ ID NO:6767); MIR1870 (SEQ ID NO:6768); MIR1871 (SEQ ID NO:6769); MIR1872 (SEQ ID NO:6770); MIR1873 (SEQ ID NO:6771); MIR1874 (SEQ ID NO:6772); MIR1875 (SEQ ID NO:6773); MIR1876 (SEQ ID NO:6774); MIR1877 (SEQ ID NO:6775); MIR1878 (SEQ ID NO:6776); MIR1879 (SEQ ID NO:6777); MIR1880 (SEQ ID NO:6778); MIR1881 (SEQ ID NO:6779); MIR1882a (SEQ ID NO:6780); MIR1882b (SEQ ID NO:6781); MIR1882c (SEQ ID NO:6782); MIR1882d (SEQ ID NO:6783); MIR1882e (SEQ ID NO:6784); MIR1882f (SEQ ID NO:6785); MIR1882g (SEQ ID NO:6786); MIR1882h (SEQ ID NO:6787); MIR1883a (SEQ ID NO:6788); MIR1883b (SEQ ID NO:6789); MIR2055 (SEQ ID NO:6790); MIR2090 (SEQ ID NO:6791); MIR2091 (SEQ ID NO:6792); MIR2092 (SEQ ID NO:6793); MIR2093 (SEQ ID NO:6794); MIR2094 (SEQ ID NO:6795); MIR2095 (SEQ ID NO:6796); MIR2096 (SEQ ID NO:6797); MIR2097 (SEQ ID NO:6798); MIR2098 (SEQ ID NO:6799); MIR2099 (SEQ ID NO:6800); MIR2100 (SEQ ID NO:6801); MIR2101 (SEQ ID NO:6802); MIR2102 (SEQ ID NO:6803); MIR2103 (SEQ ID NO:6804); MIR2104 (SEQ ID NO:6805); MIR2105 (SEQ ID NO:6806); MIR2106 (SEQ ID NO:6807); MIR2118a (SEQ ID NO:6808); MIR2118b (SEQ ID NO:6809); MIR2118c (SEQ ID NO:6810); MIR2118d (SEQ ID NO:6811); MIR2118e (SEQ ID NO:6812); MIR2118f (SEQ ID NO:6813); MIR2118g (SEQ ID NO:6814); MIR2118h (SEQ ID NO:6815); MIR2118i (SEQ ID NO:6816); MIR2118j (SEQ ID NO:6817); MIR2118k (SEQ ID NO:6818); MIR2118l (SEQ ID NO:6819); MIR2118m (SEQ ID NO:6820); MIR2118n (SEQ ID NO:6821); MIR2118o (SEQ ID NO:6822); MIR2118p (SEQ ID NO:6823); MIR2118q (SEQ ID NO:6824); MIR2118r (SEQ ID NO:6825); MIR2120 (SEQ ID NO:6826); MIR2121a (SEQ ID NO:6827); MIR2121b (SEQ ID NO:6828); MIR2122 (SEQ ID NO:6829); MIR2275a (SEQ ID NO:6830); MIR2275b (SEQ ID NO:6831); MIR2275c (SEQ ID NO:6832); MIR2275d (SEQ ID NO:6833); MIR2863a (SEQ ID NO:6834); MIR2863b (SEQ ID NO:6835); MIR2863c (SEQ ID NO:6836); MIR2864 (SEQ ID NO:6837); MIR2865 (SEQ ID NO:6838); MIR2866 (SEQ ID NO:6839); MIR2867 (SEQ ID NO:6840); MIR2868 (SEQ ID NO:6841); MIR2869 (SEQ ID NO:6842); MIR2870 (SEQ ID NO:6843); MIR2871a (SEQ ID NO:6844); MIR2871b (SEQ ID NO:6845); MIR2872 (SEQ ID NO:6846); MIR2873a (SEQ ID NO:6847); MIR2873b (SEQ ID NO:6848); MIR2873c (SEQ ID NO:6849); MIR2874 (SEQ ID NO:6850); MIR2875 (SEQ ID NO:6851); MIR2876 (SEQ ID NO:6852); MIR2877 (SEQ ID NO:6853); MIR2878 (SEQ ID NO:6854); MIR2879 (SEQ ID NO:6855); MIR2880 (SEQ ID NO:6856); MIR2905 (SEQ ID NO:6857); MIR2907a (SEQ ID NO:6858); MIR2907b (SEQ ID NO:6859); MIR2907c (SEQ ID NO:6860); MIR2907d (SEQ ID NO:6861); MIR2918 (SEQ ID NO:6862); MIR2919 (SEQ ID NO:6863); MIR2920 (SEQ ID NO:6864); MIR2921 (SEQ ID NO:6865); MIR2922 (SEQ ID NO:6866); MIR2923 (SEQ ID NO:6867); MIR2924 (SEQ ID NO:6868); MIR2925 (SEQ ID NO:6869); MIR2926 (SEQ ID NO:6870); MIR2927 (SEQ ID NO:6871); MIR2928 (SEQ ID NO:6872); MIR2929 (SEQ ID NO:6873); MIR2930 (SEQ ID NO:6874); MIR2931 (SEQ ID NO:6875); MIR2932 (SEQ ID NO:6876); MIR3979 (SEQ ID NO:6877); MIR3980a (SEQ ID NO:6878); MIR3980b (SEQ ID NO:6879); MIR3981 (SEQ ID NO:6880); MIR3982 (SEQ ID NO:6881); MIR5071 (SEQ ID NO:6882); MIR5072 (SEQ ID NO:6883); MIR5073 (SEQ ID NO:6884); MIR5074 (SEQ ID NO:6885); MIR5075 (SEQ ID NO:6886); MIR5076 (SEQ ID NO:6887); MIR5077 (SEQ ID NO:6888); MIR5078 (SEQ ID NO:6889); MIR5079a (SEQ ID NO:6890); MIR5079b (SEQ ID NO:6891); MIR5080 (SEQ ID NO:6892); MIR5081 (SEQ ID NO:6893); MIR5082 (SEQ ID NO:6894); MIR5083 (SEQ ID NO:6895); MIR5143a (SEQ ID NO:6896); MIR5143b (SEQ ID NO:6897); MIR5144 (SEQ ID NO:6898); MIR5145 (SEQ ID NO:6899); MIR5146 (SEQ ID NO:6900); MIR5147 (SEQ ID NO:6901); MIR5148a (SEQ ID NO:6902); MIR5148b (SEQ ID NO:6903); MIR5148c (SEQ ID NO:6904); MIR5149 (SEQ ID NO:6905); MIR5150 (SEQ ID NO:6906); MIR5151 (SEQ ID NO:6907); MIR5152 (SEQ ID NO:6908); MIR5153 (SEQ ID NO:6909); MIR5154 (SEQ ID NO:6910); MIR5155 (SEQ ID NO:6911); MIR5156 (SEQ ID NO:6912); MIR5157a (SEQ ID NO:6913); MIR5157b (SEQ ID NO:6914); MIR5158 (SEQ ID NO:6915); MIR5159 (SEQ ID NO:6916); MIR5160 (SEQ ID NO:6917); MIR5161 (SEQ ID NO:6918); MIR5162 (SEQ ID NO:6919); MIR5179 (SEQ ID NO:6920); MIR5337a (SEQ ID NO:6921); MIR5337b (SEQ ID NO:6922); MIR5338 (SEQ ID NO:6923); MIR5339 (SEQ ID NO:6924); MIR5340 (SEQ ID NO:6925); MIR5484 (SEQ ID NO:6926); MIR5485 (SEQ ID NO:6927); MIR5486 (SEQ ID NO:6928); MIR5487 (SEQ ID NO:6929); MIR5488 (SEQ ID NO:6930); MIR5489 (SEQ ID NO:6931); MIR5490 (SEQ ID NO:6932); MIR5491 (SEQ ID NO:6933); MIR5492 (SEQ ID NO:6934); MIR5493 (SEQ ID NO:6935); MIR5494 (SEQ ID NO:6936); MIR5495 (SEQ ID NO:6937); MIR5496 (SEQ ID NO:6938); MIR5497 (SEQ ID NO:6939); MIR5498 (SEQ ID NO:6940); MIR5499 (SEQ ID NO:6941); MIR5500 (SEQ ID NO:6942); MIR5501 (SEQ ID NO:6943); MIR5502 (SEQ ID NO:6944); MIR5503 (SEQ ID NO:6945); MIR5504 (SEQ ID NO:6946); MIR5505 (SEQ ID NO:6947); MIR5506 (SEQ ID NO:6948); MIR5507 (SEQ ID NO:6949); MIR5508 (SEQ ID NO:6950); MIR5509 (SEQ ID NO:6951); MIR5510 (SEQ ID NO:6952); MIR5511 (SEQ ID NO:6953); MIR5512a (SEQ ID NO:6954); MIR5512b (SEQ ID NO:6955); MIR5513 (SEQ ID NO:6956); MIR5514 (SEQ ID NO:6957); MIR5515 (SEQ ID NO:6958); MIR5516a (SEQ ID NO:6959); MIR5516b (SEQ ID NO:6960); MIR5517 (SEQ ID NO:6961); MIR5518 (SEQ ID NO:6962); MIR5519 (SEQ ID NO:6963); MIR5521 (SEQ ID NO:6964); MIR5522 (SEQ ID NO:6965); MIR5523 (SEQ ID NO:6966); MIR5524 (SEQ ID NO:6967); MIR5525 (SEQ ID NO:6968); MIR5526 (SEQ ID NO:6969); MIR5527 (SEQ ID NO:6970); MIR5528 (SEQ ID NO:6971); MIR5529 (SEQ ID NO:6972); MIR5530 (SEQ ID NO:6973); MIR5531 (SEQ ID NO:6974); MIR5532 (SEQ ID NO:6975); MIR5533 (SEQ ID NO:6976); MIR5534a (SEQ ID NO:6977); MIR5534b (SEQ ID NO:6978); MIR5535 (SEQ ID NO:6979); MIR5536 (SEQ ID NO:6980); MIR5537 (SEQ ID NO:6981); MIR5538 (SEQ ID NO:6982); MIR5539a (SEQ ID NO:6983); MIR5539b (SEQ ID NO:6984); MIR5540 (SEQ ID NO:6985); MIR5541 (SEQ ID NO:6986); MIR5542 (SEQ ID NO:6987); MIR5543 (SEQ ID NO:6988); MIR5544 (SEQ ID NO:6989); MIR5788 (SEQ ID NO:6990); MIR5789 (SEQ ID NO:6991); MIR5790 (SEQ ID NO:6992); MIR5791 (SEQ ID NO:6993); MIR5792 (SEQ ID NO:6994); MIR5793 (SEQ ID NO:6995); MIR5794 (SEQ ID NO:6996); MIR5795 (SEQ ID NO:6997); MIR5796 (SEQ ID NO:6998); MIR5797 (SEQ ID NO:6999); MIR5798 (SEQ ID NO:7000); MIR5799 (SEQ ID NO:7001); MIR5800 (SEQ ID NO:7002); MIR5801 (SEQ ID NO:7003); MIR5802 (SEQ ID NO:7004); MIR5803 (SEQ ID NO:7005); MIR5804 (SEQ ID NO:7006); MIR5805 (SEQ ID NO:7007); MIR5806 (SEQ ID NO:7008); MIR5807 (SEQ ID NO:7009); MIR5808 (SEQ ID NO:7010); MIR5809 (SEQ ID NO:7011); MIR5810 (SEQ ID NO:7012); MIR5811 (SEQ ID NO:7013); MIR5812 (SEQ ID NO:7014); MIR5813 (SEQ ID NO:7015); MIR5814 (SEQ ID NO:7016); MIR5815 (SEQ ID NO:7017); MIR5816 (SEQ ID NO:7018); MIR5817 (SEQ ID NO:7019); MIR5818 (SEQ ID NO:7020); MIR5819 (SEQ ID NO:7021); MIR5820 (SEQ ID NO:7022); MIR5821 (SEQ ID NO:7023); MIR5822 (SEQ ID NO:7024); MIR5823 (SEQ ID NO:7025); MIR5824 (SEQ ID NO:7026); MIR5825 (SEQ ID NO:7027); MIR5826 (SEQ ID NO:7028); MIR5827 (SEQ ID NO:7029); MIR5828 (SEQ ID NO:7030); MIR5829 (SEQ ID NO:7031); MIR5830 (SEQ ID NO:7032); MIR5831 (SEQ ID NO:7033); MIR5832 (SEQ ID NO:7034); MIR5833 (SEQ ID NO:7035); MIR5834 (SEQ ID NO:7036); MIR5835 (SEQ ID NO:7037); MIR5836 (SEQ ID NO:7038); MIR5837 (SEQ ID NO:7039); MIR6245 (SEQ ID NO:7040); MIR6246 (SEQ ID NO:7041); MIR6247 (SEQ ID NO:7042); MIR6248 (SEQ ID NO:7043); MIR6249a (SEQ ID NO:7044); MIR6249b (SEQ ID NO:7045); MIR6250 (SEQ ID NO:7046); MIR6251 (SEQ ID NO:7047); MIR6252 (SEQ ID NO:7048); MIR6253 (SEQ ID NO:7049); MIR6254 (SEQ ID NO:7050); MIR6255 (SEQ ID NO:7051); MIR6256 (SEQ ID NO:7052); MIR7692 (SEQ ID NO:7053); MIR7693 (SEQ ID NO:7054); MIR7694 (SEQ ID NO:7055); and MIR7695 (SEQ ID NO:7056).

When used, any generic description of an miRNA refers to any of its gene family members, unless otherwise indicated. A “gene family” refers to a group of genes that have the same miRNA coding sequence. Typically, members of a gene family are identified by a number or letter following the initial designation. For example, miR-16-1 and miR-16-2 are members of the miR-16 gene family and “mir-7” refers to miR-7-1, miR-7-2 and miR-7-3. Likewise, “let-7,” for example, refers to let-7a-1, let7-a-2, let-7b, let-7c, let-7d, let-7e, let-7f-1, and let-7f-2.

The artificially-designed RNA disclosed herein can include RNA flanking sequences. “RNA flanking sequences” refer to nucleotide sequences including RNA processing elements that flank one or both sides of the Drosha cutting site.

“miRNA flanking sequence” refers to nucleotide sequences including miRNA processing elements. miRNA processing elements are the minimal nucleic acid sequences which contribute to the production of mature miRNA from precursor miRNA. Often these elements are located within a 40 nucleotide sequence that flanks a miRNA stem-loop structure. In some instances the miRNA processing elements are found within a stretch of nucleotide sequences of between 5 and 4,000 nucleotides in length that flank a miRNA stem-loop structure.

Thus, in some embodiments the flanking sequences are 5-4,000 nucleotides in length. As a result, the length of the precursor molecule may be, in some instances at least about 150 nucleotides or 270 nucleotides in length. The total length of the precursor molecule, however, may be greater or less than these values. In other embodiments the minimal length of the miRNA flanking sequence is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 and any integer there between. In other embodiments the maximal length of the miRNA flanking sequence is 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900 4,000 and any integer there between.

The miRNA flanking sequences may be native/endogenous miRNA flanking sequences or artificial miRNA flanking sequences. A native/endogenous miRNA flanking sequence is a nucleotide sequence that is ordinarily associated in naturally existing systems with miRNA sequences, i.e., these sequences are found within the genomic sequences surrounding the minimal miRNA hairpin in vivo. Artificial miRNA flanking sequences are nucleotide sequences that are not found to be flanking to miRNA sequences in naturally existing systems. The artificial miRNA flanking sequences may be flanking sequences found naturally in the context of other miRNA sequences. Alternatively they may be composed of minimal miRNA processing elements which are found within naturally occurring flanking sequences and inserted into other random nucleic acid sequences that do not naturally occur as flanking sequences or only partially occur as natural flanking sequences.

The miRNA flanking sequences within the precursor miRNA molecule may flank one or both sides of the stem-loop structure encompassing the miRNA sequence. Thus, one end (i.e., 5′) of the stem-loop structure may be adjacent to a single flanking sequence and the other end (i.e., 3′) of the stem-loop structure may not be adjacent to a flanking sequence. Particular structures have flanking sequences on both ends of the stem-loop structure. The flanking sequences may be directly adjacent to one or both ends of the stem-loop structure or may be connected to the stem-loop structure through a linker, additional nucleotides or other molecules.

In some instances the pri-miRNA molecule may include more than one stem-loop structure. The multiple stem-loop structures may be linked to one another through a linker, such as, for example, a nucleic acid linker or by a miRNA flanking sequence or other molecule or some combination thereof.

In particular embodiments, useful interfering RNAs can be designed with a number of software programs, e.g., the OligoEngine RNA design tool available at www.oligoengine.com. RNAs within this context can be about, e.g., 19-33 basepairs in length for the double-stranded portion. In some embodiments, the RNAs are hairpin RNAs having an about 19-33 bp stem and an about 4-34 nucleotide loop. Particular RNAs are highly specific for a region of a target gene and may comprise 19-33 bp fragments of a target gene mRNA that has at least one, at least two, or at least three, bp mismatches with a nontargeted gene-related sequence. In some embodiments, the RNAs do not bind to RNAs having more than 3 mismatches with the target region.

The artificial RNAs disclosed herein are formed from a polymer of nucleotides (i.e. molecules comprising a sugar (e.g. ribose) linked to a phosphate group and to an exchangeable organic base, which is either a substituted pyrimidine (e.g. cytosine (C), or uracil (U)) or a substituted purine (e.g. adenine (A) or guanine (G)). As used herein, the term nucleotides also can include polynucleosides (i.e. a polynucleotide minus the phosphate) and any other organic base containing polymer.

The artificial miRNAs can also encompass nucleotides with substitutions or modifications, such as in the bases and/or sugars. Modified bases include any base that is chemically distinct from the naturally occurring bases typically found in RNA (C, G, A, and U), but which share basic chemical structures with these naturally occurring bases. The modified nucleotide base may be, for example, dihydrouracil, pseudouracil, 2-thiouracil, 4-thiouracil, 5-aminouracil, 5-(C₁-C₆)-alkyluracil, 5-(C₂-C₆)-alkenyluracil, 5-(C₂-C₆)-alkynyluracil, 5-(hydroxymethyl)uracil, 5-chlorouracil, 5-fluorouracil, 5-bromouracil, 5-hydroxycytosine, 5-(C₁-C₆)-alkylcytosine, 5-(C₂-C₆)-alkenylcytosine, 5-(C₂-C₆)-alkynylcytosine, 5-chlorocytosine, 5-fluorocytosine, 5-bromocytosine, N²-dimethylguanine, 2,4-diamino-purine, 8-azapurine, a substituted 7-deazapurine, 7-deaza-7-substituted and/or 7-deaza-8-substituted purine, 5-hydroxymethylcytosine, N4-alkylcytosine, N4-ethylcytosine, 5-hydroxydeoxycytidine, 5-hydroxymethyldeoxycytidine, N4-alkyldeoxycytidine, N4-ethyldeoxycytidine, 6-thiodeoxyguanosine, deoxyribonucleosides of nitropyrrole, C5-propynylpyrimidine, diaminopurine, 2,6-diaminopurine, inosine, 5-methylcytosine, 2-aminopurine, 2-amino-6-chloropurine, hypoxanthine or other modifications of a natural nucleoside bases.

The artificial RNAs can also encompass various chemical modifications and substitutions, in comparison to natural RNA involving phosphodiester internucleotide bridges and/or β-D-ribose units. Replacing a phosphodiester bridge located at the 3′ and/or the 5′ end of a nucleotide can make artificial RNAs disclosed herein more resistant to degradation (i.e., are stabilized). Exemplary modified internucleotide bridges include phosphorothioate, phosphorodithioate, NR^1R2-phosphoramidate, boranophosphate, α-hydroxybenzyl phosphonate, phosphate-(C₁-C₂₁)—O-alkyl ester, phosphate-[(C₆-C₁₂)aryl-(C₁-C₂₁)—O-alkyl]ester, (C₁-C₈)alkylphosphonate and/or (C₆-C₁₂)arylphosphonate bridges, (C₇-C₁₂)-a-hydroxymethyl-aryl, wherein (C₆-C₁₂)aryl, (C₆-C₂₀)aryl and (C₆-C₁₄)aryl are optionally substituted by halogen, alkyl, alkoxy, nitro, cyano, and where R¹ and R² are, independently of each other, hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₂₀)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl, hydrogen, (C₁-C₈)-alkyl, (C₁-C₄)-alkyl and/or methoxyethyl, or R¹ and R² form, together with the nitrogen atom carrying them, a 5-6-membered heterocyclic ring which can additionally contain a further heteroatom from the group O, S and N. Dephospho bridges can also be used. Dephospho bridges are described, for example, in Uhlmann and Peyman in “Methods in Molecular Biology”, Vol. 20, “Protocols for Oligonucleotides and Analogs”, Agrawal, Ed., Humana Press, Totowa 1993, Chapter 16, pp. 355 ff). Exemplary dephospho bridges include formacetal, 3′-thioformacetal, methylhydroxylamine, oxime, methylenedimethyl-hydrazo, dimethylenesulfone and/or silyl groups.

Beta-ribose units can be replaced by modified sugar units such as 3-D-ribose, β-D-2′-deoxyribose, L-2′-deoxyribose, 2′-F-2′-deoxyribose, 2′-F-arabinose, 2′-O—(C₁-C₆)alkyl-ribose, 2′-O—(C₁-C₆)alkyl-ribose, 2′-O-methylribose, 2′-O—(C₂-C₆)alkenyl-ribose, 2′[O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl]-ribose, 2′—NH₂-2′-deoxyribose, β-D-xylo-furanose, α-arabinofuranose, 2,4-dideoxy-β-D-erythro-hexo-pyranose or carbocyclic and/or open-chain sugar analogs and/or bicyclosugar analogs.

Sugar phosphate units from the sugar phosphate backbone can also be replaced by other units such as “morpholino-derivative” oligomers (see, for example, Stirchak et al. (1989) Nucleic Acids Res 17:6129-41); polyamide nucleic acids (PNA; see, for example, Nielsen et al. (1994) Bioconjug Chem 5:3-7) such as by 2-aminoethylglycine; peptide nucleic acids with phosphate groups (PHONA); locked nucleic acids (LNA); and/or nucleotides having backbone sections with alkyl linkers or amino linkers. Alkyl linkers can be branched or unbranched, substituted or unsubstituted, and chirally pure or a racemic mixture.

Artificial RNAs disclosed herein can also be conjugated to lipophilic or lipid moieties. Exemplary lipophilic or lipid moieties include cholesteryls, modified cholesteryls, cholesterol derivatives, reduced cholesterols, substituted cholesterols, cholestans, C_1-6 alkyl chains, cholic acid, taurocholic acid, deoxycholate, oleyl litocholic acid, oleoyl cholenic acid, glycolipids, phospholipids, sphingolipids, isoprenoids, saturated fatty acids, unsaturated fatty acids or fatty acid esters. The lipophilic or lipid moieties can be attached via any suitable direct or indirect linkage such as, without limitation, by an ester or an amide. Linkages can include spacer moieties, for example one or more nucleotide residues, oligoethyleneglycol, triethyleneglycol, hexaethylenegylcol or an alkane-diol, such as butanediol.

Artificial RNAs disclosed herein can also be conjugated to Nuclear Localization Signals (NLS). “Nuclear localization signals” are sequences (in some embodiments amino acid sequences) that can direct artificial RNAs in the cytoplasm of a cell across the nuclear membrane and into the nucleus of the cell. A nuclear localization signal can also target the exterior surface of a cell. Thus, a single nuclear localization signal can direct the artificial RNA with which it is associated to the exterior of a cell and to the nucleus of a cell. Nuclear localization signals are generally basic, comprise a short sequence of 4-8 amino acids and are typically rich in lysine and arginine residues while also often comprising proline residues.

While particular RNA sequences are described, the current disclosure also encompasses RNA sequences that hybridize with the specifically disclosed RNA sequences. An RNA sequence “hybridizes” to another RNA sequences when a single stranded form of the RNA sequence anneals to the other RNA sequence under the appropriate conditions of temperature and solution ionic strength. Hybridization and washing conditions are well known and exemplified in Sambrook, J., Fritsch, E. F. and Maniatis, T. Molecular Cloning: A Laboratory Manual, Second Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), particularly Chapter 11 and Table 11.1 therein (incorporated by reference herein for its teachings regarding the same). The conditions of temperature and ionic strength determine the “stringency” of the hybridization. Stringency conditions can be adjusted to screen for moderately similar RNA sequences to highly similar RNA sequences. Post-hybridization washes determine stringency conditions. One set of hybridization conditions to demonstrate that RNA sequences hybridize uses a series of washes starting with 6×SSC, 0.5% SDS at room temperature for 15 min, then repeated with 2×SSC, 0.5% SDS at 45° C. for 30 min, and then repeated twice with 0.2×SSC, 0.5% SDS at 50° C. for 30 min. Stringent conditions use higher temperatures in which the washes are identical to those above except for the temperature of the final two 30 min washes in 0.2×SSC, 0.5% SDS is increased to 60° C. Highly stringent conditions use two final washes in 0.1 SSC, 0.1% SDS at 65° C. Those of ordinary skill in the art will recognize that these temperature and wash solution salt concentrations may be adjusted as necessary according to factors such as the length of the tested RNA sequences.

RNA sequences that share a % identity with the RNA sequences explicitly disclosed herein are also within the scope of the present disclosure. The % identity is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. As is known in the art, “% identity” refers to a relationship between two or more RNA sequences, as determined by comparing the sequences. In the art, “identity” also means the degree of sequence relatedness between RNA sequences as determined by the match between strings of such sequences. “Identity” (often referred to as “similarity”) can be readily calculated by known methods, including (but not limited to) those described in:Computational Molecular Biology (Lesk, A. M., ed.) Oxford University Press, NY (1988); Biocomputing:lnformatics and Genome Projects (Smith, D. W., ed.) Academic Press, NY (1994); Computer Analysis of Sequence Data, Part I (Griffin, A. M., and Griffin, H. G., eds.) Humana Press, NJ (1994); Sequence Analysis in Molecular Biology (Von Heijne, G., ed.) Academic Press (1987); and Sequence Analysis Primer (Gribskov, M. and Devereux, J., eds.) Oxford University Press, NY (1992), each incorporated by reference herein for its teachings regarding the same. Preferred methods to determine identity are designed to give the best match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Sequence alignments and percent identity calculations may be performed using the Megalign program of the LASERGENE bioinformatics computing suite (DNASTAR, Inc., Madison, Wis.). Multiple alignment of the sequences can also be performed using the Clustal method of alignment (Higgins and Sharp (1989) CABIOS. 5:151-153, incorporated by reference herein for its teaching regarding the same) with default parameters (GAP PENALTY=10, GAP LENGTH PENALTY=10). Relevant programs also include the GCG suite of programs (Wisconsin Package Version 9.0, Genetics Computer Group (GCG), Madison, Wis.); BLASTP, BLASTN, BLASTX (Altschul, et al., J. Mol. Biol. 215:403-410, 1990, incorporated by reference herein for its teaching regarding the same); DNASTAR (DNASTAR, Inc., Madison, Wis.); and the FASTA program incorporating the Smith-Waterman algorithm (Pearson, Comput. Methods Genome Res., [Proc. Int. Symp.] (1994), Meeting Date 1992, 111-20. Editor(s):Suhai, Sandor. Publisher:Plenum, New York, N.Y. incorporated by reference herein for its teaching regarding the same). Within the context of this disclosure, and where not otherwise specified, it will be understood that where sequence analysis software is used for analysis, the results of the analysis are based on the “default values” of the program referenced. As used herein “default values” will mean any set of values or parameters which originally load with the software when first initialized.

IV. Production of Artificial RNAs and/or Drosha Protein

General texts which describe molecular biological techniques to form nucleotide sequences and proteins include Sambrook, Molecular Cloning:a Laboratory Manual (2nd ed.) Vols. 1-3, Cold Spring Harbor Laboratory, (1989); Current Protocols in Molecular Biology Ausubel, ed. John Wiley & Sons, Inc., New York (1997); Laboratory Techniques in Biochemistry and Molecular Biology: Hybridization with Nucleic Acid Probes, Part 1. Theory and Nucleic Acid Preparation, P. Tijssen, ed. Elsevier, N.Y. (1993); Berger and Kimmel, Guide to Molecule Cloning Techniques Methods in Enzymology volume 152 Academic Press, Inc., San Diego, Calif. These texts describe the synthesis of nucleic acids and proteins as well as mutagenesis, the use of vectors, promoters and many other relevant topics related to generation and expression of genes encoding RNA, miRNA and protein. Techniques for isolation, purification and manipulation of nucleic acids, RNA, miRNA, genes, and proteins such as subcloning into expression vectors, labeling probes, and nucleotide hybridization are also described in the texts above and are well known to one of ordinary skill in the art.

The RNAs (including, without limitation, artificial RNAs, miRNAs and artificial miRNAs) and proteins disclosed herein can be formed by any technique known to one of ordinary skill in the art, including by chemical synthesis, enzymatic production or recombinant methods.

Chemical synthesis can be achieved by the diester method, the triester method, the phosphorylase method and/or by solid-phase chemistry. For example, chemical synthesis of RNAs can be performed using phosphotriester, phosphite or phosphoramidite chemistry and solid phase techniques such as described in EP 266,032 or via deoxynucleoside H-phosphonate intermediates as described in U.S. Pat. No. 5,705,629, each incorporated herein by reference for their teachings regarding the same.

A non-limiting example of enzymatic production includes amplification reactions such as polymerase chain reactions (PCR; see for example, U.S. Pat. Nos. 4,683,202 and 4,682,195, each incorporated by reference for their teachings regarding the same), or enzymatic synthesis as described in U.S. Pat. No. 5,645,897, incorporated by reference herein for its teachings regarding the same.

Recombinant RNAs and recombinant proteins include those produced from cells transformed by an exogenous DNA construct encoding the desired RNA or protein. Recombinant production methods are also well known in the art. For example, RNA molecules or proteins can be encoded by a nucleic acid molecule within a vector. The term “vector” refers to a carrier nucleic acid molecule into which a nucleic acid sequence can be inserted for introduction into a cell where it can be replicated. Vectors include plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). One of ordinary skill in the art is well equipped to construct appropriate vectors through standard recombinant techniques. In addition to encoding RNA or proteins as disclosed herein, vectors can also encode sequences such as tags or targeting molecules. Targeting molecules can direct expressed RNA or protein to a particular location in a cell, to an organ, tissue, distant cell, or other location in a subject's body.

There are a number of ways in which vectors can be introduced into cells. Exemplary methods include microinjection, electroporation, lipid transfection, liposome mediated transfection, calcium phosphate transfection, calcium phosphate precipitation, DEAE-dextran followed by polyethylene glycol, sonic loading, microprojectile bombardment; or agitation with silicon carbide fibers. Recombinant methods can also be performed in cell free systems so long as the reagents for generating the RNA molecule are present. Additional methods for artificial RNA synthesis can be found in, without limitation, U.S. Pat. Nos. 4,659,774; 4,704,362; 4,816,571; 4,959,463; 5,141,813; 5,221,619; 5,264,566; 5,428,148; and U.S. Pat. Nos. 5,554,744; 5,574,146; 5,583,013; and 5,602,244 each of which is incorporated by reference herein for their teachings regarding the same.

V. Methods of Use

RNA, including miRNA, have been implicated in a wide variety of diseases and disorders. miRNA, artificial miRNA and Drosha up- and down-regulation disclosed herein can be used in therapeutic applications directed to, without limitation, acne, ADHD, adult-onset diabetes, age spots, age-related hearing loss, age-related macular degeneration, age-related vision change, AIDS, alcohol withdrawal, alcoholism, allergic rhinitis, allergies, alopecia, altitude sickness, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anemia, aneurism, angina, anxiety disorder, aplastic anemia, areata, arthritis, asthma, atherosclerosis, athlete's foot, atopic dermatitis, atrial fibrillation, autoimmune disease, Behcet's syndrome, Bell's palsy, bipolar disorder, bone disease, bradycardia, cardiovascular disease, cataracts, celiac disease, cerebral palsy, chloasma, congestive heart failure, conjunctivitis, cornea keratitis, Crohn's disease, cystic fibrosis, dandruff, dementia, depressive disorders, dermatitis, diabetes, diabetes mellitus, type 1, diabetes mellitus, type 2, dry-eye syndrome, dry skin, dysthymia, eclampsia, eczema, endocarditis, endometriosis, enlarged prostate, epilepsy, erectile dysfunction, essential tremor, fibroids, fibromyalgia, glaucoma, Graves disease, Guillain-Barre syndrome, hemophilia, high blood pressure, high cholesterol, Huntington's disease, hyperthyroidism, hypoparathyroidism, hypothyroidism, immune thrombocytopenic purpura, inflammatory bowel disease, insomnia, irritable bowel syndrome, juvenile arthritis, keloids, lactose intolerance, liver spots, locomotor dysfunction, lupus, major depression, manic depression, melasma, memory loss, multiple sclerosis, muscular dystrophy, myasthenia gravis, myocardial infarction, myocarditis, myopia, narcolepsy, obesity, obsessive-compulsive disorder, optic nerve swelling, osteoarthritis, osteoporosis, Paget's disease, Parkinson's disease, pain, panic disorder, peripheral vascular disease, pernicious anemia, phobia, pigmentation disorders, post-partum depression, post-traumatic stress disorder, preeclampsia, pregnancy-induced hypertension, presbyopia, psoriasis, psoriatic arthritis, renal failure, restless legs syndrome, Reye's syndrome, rheumatoid arthritis, rosacea, scars, schizophrenia, sciatica, scleroderma, seizures, sexual dysfunction, sickle cell anemia, skin blemishes, spider veins, sterility, stroke, sun-damaged skin, systemic lupus, Tay-Sachs disease, tendonitis, tennis elbow, tension headache, thrombocytopenia, tinnitus, ulcer, urinary incontinenece, varicose veins, vitiligo, and wrinkles.

miRNA, artificial miRNA and Drosha up- and down-regulation disclosed herein can be used in therapeutic applications directed to treatment of various cancers including, without limitation, bladder cancer, blood cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, gastrointestinal cancer, gum cancer, head cancer, kidney cancer, liver cancer, lung cancer, nasopharynx cancer, neck cancer, ovarian cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, tongue cancer, uterine cancer, neoplastic cancer, malignant cancer; carcinomas; sarcomas; lymphomas; Hodgkin's lymphomas; non-Hodgkin's lymphomas; and leukemias.

miRNA, artificial miRNA and Drosha up- and down-regulation disclosed herein can be used in therapeutic applications directed to infectious diseases, i.e., those arising from the presence of a foreign microorganism in the body. A microbial antigen, as used herein, is an antigen of a microorganism. Microorganisms include but are not limited to, infectious viruses, infectious bacteria, and infectious fungi.

Examples of infectious viruses include: Retroviridae (e.g. human immunodeficiency viruses, such as HIV-1 (also referred to as HTLV-III, LAV or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV-LP; Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses); Rhabdoviradae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvovirida (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxyiridae (variola viruses, vaccinia viruses, pox viruses); and lridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the agents of non-A, non-B hepatitis (class 1=internally transmitted; class 2=parenterally transmitted (i.e. Hepatitis C); Norwalk and related viruses, and astroviruses).

Examples of infectious bacteria include: Helicobacter pyloris, Borelia burgdorferi, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellulare, M. kansaii, M. gordonae), Staphylococcus aureus, Neisseria gonorrhoeae, N. meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A S.), S. agalactiae (Group B S.), S. viridans group, S. faecalis, S. bovis, S. pneumoniae, pathogenic Campylobacter sp., Enterococcus sp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium sp., Erysipelothrix rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Treponema palladium, Treponema pertenue, Leptospira, Rickettsia, and Actinomyces israelli.

Examples of infectious fungi include: Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, and Candida albicans. Other infectious organisms (i.e., protists) include: Plasmodium such as Plasmodium falciparum, P. malariae, P. ovale, and P. vivax and Toxoplasma gondii.

Other exemplary infections include athlete's foot, chickenpox, common cold, diarrheal diseases, flu, genital herpes, malaria, meningitis, pneumonia, sinusitis, various skin diseases, strep throat, tuberculosis, urinary tract infections, vaginal infections, viral hepatitis, and prion diseases.

miRNAs that up-regulate cell growth include miR-31, miR-150, miR-187, miR-125a, miR-190, miR-191, miR-193, miR-204, and miR-218. Accordingly, in conditions with less than optimal cell growth, such as degenerative diseases, including neural degeneration, multiple sclerosis, or macular degeneration, it would be beneficial to up-regulate these miRNAs. Of these miRNAs, for example, miR-31 and miR-150 are semi-rigid and miR-193 is mis-matched. When an up-regulation of cell growth is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell growth is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs that down-regulate cell growth include miR-21 and miR-24. Of these miRNAs, miR-21 is semi-rigid and miR-24 is rigid. Accordingly, in conditions with excessive cell growth, such as breast cancer, cervical cancer, colon cancer, liver cancer, lung cancer, prostate cancer, skin cancer, stomach cancer, and testicular cancer, it would be beneficial to up-regulate these miRNAs. When a down-regulation of cell growth is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell growth is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs such as miR-7, miR-19a, miR-23, miR-24, miR-27a, miR-31, miR-32, miR-134, miR-140, miR-150, miR-192, and miR-193 reduce cell viability. Of these miRNAs, for example, miR-7 and miR-23 are semi-rigid, and miR-19a is rigid. In conditions related to increased cell viability, such as cancerous tumors, hyperthyroidism, overactive adrenal gland, and hyperlipidemia, it would be beneficial to up-regulate these miRNAs in order to reduce cell viability. When a down-regulation of cell viability is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell viability is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs such as miR-107, miR-133, miR-137, miR-152, miR-155, miR-181a, miR-191, miR-203, and miR-215 increase cell viability. Of these miRNAs, for example, miR-155, miR-191, miR-203, and miR-215 are semi-rigid. Accordingly, in conditions with decreased cell viability, such as cirrhosis of the liver, HIV, and cell degeneration, it would be beneficial to up-regulate these miRNAs in order to increase cell viability. When an up-regulation of cell viability is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell viability is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

An increase in the percentage of apoptotic cells is caused by miR-338, miR-27a, miR-128, miR-23a, miR-324, miR-22, miR-181a, mmu-miR-293, mmu-miR-412, miR-196, miR-31, Let-7d, miR-23b, mu-miR-290, miR-217, miR-199, miR-24, miR-214, and miR-198. Of these miRNAs, miR-23a and miR-338 are semi-rigid and miR-27a is quasi-rigid, for example. Accordingly, in conditions related to insufficient apoptosis, such as carcinomas, bone cancers, tumors, glioma, thyroid cancer, and throat cancer, it would be beneficial to up-regulate these miRNAs. When an up-regulation of apoptosis is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of apoptosis is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs that decrease the percentage of apoptotic cells include miR-105, miR-34a, miR-96, mmu-miR-292, miR-126, miR-137, and miR-101. Of these miRNAs, miR-96 and miR-126 are semi-rigid. Accordingly, in conditions related to excessive apoptosis, such as HIV, neurodegenerative diseases, hematologic diseases, and tissue damage, it would be beneficial to up-regulate these miRNAs. When a down-regulation of apoptosis is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of apoptosis is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including miR-31 and miR-214 reduce cell proliferation. Of these miRNAs, miR-31 is semi-rigid, and miR-214 is mis-matched. When a down-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

An increase in cell proliferation is caused by miRNAs such as miR-7, miR-1-2, miR-148, miR-195, miR-196, miR-199a, miR-204, miR-210, miR-211, miR-212, miR-215, miR-216, miR-218, miR-296, and miR-321. Of these miRNAs, miR-7, miR-148, and miR-195 are semi-rigid, for example. When an up-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs such as miR-100, miR-130a, miR-211, miR-212, miR-213, miR-215, miR-224, miR-292, miR-320, miR-324, miR-325, miR-330, miR-338, miR-369, miR-370, and miR-99a increase the proliferation of Prostate 22Rv1 cells. Of these miRNAs, miR-211 and miR-212 are quasi-rigid. When an up-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs such as miR-10b and miR-152 decrease proliferation of Prostate 22Rv1 cells. Of these miRNAs, miR-10b is rigid, and miR-152 is semi-rigid. When a down-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including miR-210 and miR-216 increase the proliferation of skin TE354T cells. Of these miRNAs, miR-210 and miR-216 are quasi-rigid. When an up-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including Let-7a, Let-7b, Let-7g, miR-10a, miR-10b, miR-133b, miR-155, miR-15a, miR-16, miR-181a, miR-182, miR-193, miR-194, miR-196, mi-204, miR-23a, miR-24, miR-25, miR-92, and miR-95 decrease proliferation of skin TE354T cells. Of these miRNAs, let-7a is semi-rigid, and miR-181a is quasi-rigid. When a down-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including miR-216, miR-217, and miR-294 increase the proliferation of breast MCF12a cells. Of these miRNAs, miR-216 is quasi-rigid, and miR-217 is semi-rigid. When an up-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including Let-7a, Let-7b-1, Let-7c, Let-7d, miR-10a, miR-10b, miR-133a, miR-152, miR-153, miR-155, miR-16, miR-181a, miR-183, miR-184, miR-186, miR-191, miR-200b, miR-412, and miR-9 decrease proliferation of breast MCF12a cells. Of these miRNAs, let-7c is quasi-rigid, miR-152 is semi-rigid, and miR-10a is rigid. When a down-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs including miR-129, miR-326, miR-331, miR-338, miR-341, miR-370, and miR-92 increase the proliferation of lung A549 cells. Of these miRNAs, mir-129 is semi-rigid, and miR-370 is quasi-rigid. When an up-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When a down-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

miRNAs such as Let-7a-1, miR-133a-2, miR-142, miR-187, miR-199a-1, miR-206, miR-211, miR-222, miR-223, miR-23b, miR-298, miR-328, miR-342, and miR-371 decrease proliferation of lung A549 cells. Of these miRNAs, miR-187 is semi-rigid, and miR-211 is quasi-rigid. When a down-regulation of cell proliferation is intended, mis-matches at positions 5 and/or 9-12 from the Drosha cutting site of these miRNAs can be removed to render them less susceptible to fluctuating Drosha expression levels. When an up-regulation of cell proliferation is intended, additional mis-matches can be introduced at positions 5 and/or 9-12 from the Drosha cutting site to render the miRNA more susceptible to fluctuating Drosha expression levels.

Lupus-related miRNAs include miR-301, miR-199, miR-95, miR-105, mu-miR-290, miR-215, miR-188, miR-186, miR-211, miR-331, miR-137, miR-21, miR-223, and miR-342. miRNAs that may be related to prion diseases include miR-95, miR-135a, miR-7, miR-9, miR-27a, miR-130a, miR-16, miR-26a, and miR-24. miRNAs that are potentially associated with stroke include Let-7F-2, miR-16, miR-138, miR-139, miR30A, miR-31, miR-140, miR-298, miR-28, and miR-291-5P.

An additional aspect of the current disclosure is the design of drugs for use in the central nervous system (anti-depressants; anti-anxiety; anti-Alzheimer's; anti-Parkinson's; etc.) that have low activity in the liver. These drugs would be RNA-based with mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

Orally-administered RNA-based therapeutics are processed through the liver before reaching other sites of action. Introduction of mis-matches at positions 5 and/or 9-12 from the Drosha cutting site can minimize the RNA's effect in the liver while maintaining an effect in other targets of interest with higher Drosha expression. Accordingly, these drugs would be RNA-based with mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

Alternatively, RNA-based drugs that target the liver could have mis-matches removed to increase potency in the liver. Such RNA-based drugs could be used as therapies for, without limitation, obesity, alcohol metabolism, altering drug processing and/or glycogen storage. In particular embodiments, these drugs would be RNA-based with mis-matches removed at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2 or 3 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site.

For applications where a local effect of an RNA therapy is desired, the secondary structure can be altered to minimize the effect on surrounding tissues relative to the target tissue. For example the intestine has high Drosha expression levels compared to the liver and pancreas, so a mismatched, highly mis-matched or fully mis-matched RNA administered to the intestine would show relatively high levels in the intestine, whereas any RNA that is diffused or transported to the liver and/or pancreas would have a minimal effect in the those organs, thus reducing the risk of side effects. Applications include obesity medications that inhibit uptake of nutrients by the intestine, as well as other gastric conditions, intestinal parasites, cancer, irritable bowel syndrome, lactose intolerance, etc. These drugs would be RNA-based with mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

As another example, the ovaries have relatively high drosha expression levels compared to the uterus. For RNA therapeutics specifically targeting the ovaries (such as potential fertility treatments) RNA can be designed with mismatches incorporated to minimize the effect on the uterus as well as surrounding tissues, while still having an effect on the targeted ovaries. These drugs would be RNA-based with mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

As another example, Drosha levels vary throughout T-cell development, where young T-cells have high Drosha expression levels, which decrease as the T-cells mature. RNA therapeutics can be designed with or without mismatches in the positions 5 and/or 9-12 nucleotides from the Drosha cutting site to target mature or young T-cells respectively. This could be of importance in any therapeutic involving the immune response, such as AIDS, allergies, cancer, parasites, viral and bacterial infections, auto-immune diseases, etc. (e.g., the majority of all diseases). Embodiments targeting young T-cells would have mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In embodiments targeting mature T-cells, mis-matches would be removed at one or more of positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site.

In further examples, Drosha levels vary during many types of cellular differentiation (such as neuronal differentiation), with a maximum expression 6-12 days after differentiation begins. miRNAs for over expression can be designed (i) without mismatches in the 5, and 9-12 positions to maintain constant levels throughout the differentiation process, or (ii) alternatively with mismatches to maximize the effect specifically for the 6-12 day time point. In these embodiments, mis-matches would be removed at one or more of positions 5 and/or 9-12 from the Drosha cutting site to maintain constant levels. In particular embodiments, 1, 2, 3, 4, or 5 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are removed at positions 5 and/or 9-12 from the Drosha cutting site. In further embodiments, mis-matches would be introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site to target the 6-12 day period. In these particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

The current disclosure also applies to the tissue culture environment. In the tissue culture environment several cell types are grown simultaneously in the same environment, e.g. embryonic stem cells are commonly grown on a layer of irradiated mouse embryonic fibroblasts. Depending on the stage the embryonic cells are in, RNA that are overexpressed can be tailored to minimize the effect on other cell types that are present.

As noted, many cancer cells have high Drosha expression levels. Accordingly, miRNA therapeutics can be designed that are maximally effective in the cancerous cells while having fewer effects in healthy cells. In these embodiments, the miRNA would have mis-matches introduced at one or more of positions 5 and/or 9-12 from the Drosha cutting site to target the cancer cells. In these particular embodiments, 1, 2, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site. In particular embodiments, 3, 4, or 5 mis-matches are introduced at positions 5 and/or 9-12 from the Drosha cutting site.

In therapeutic applications, an effective amount of miRNA, artificial miRNA, Drosha protein or Drosha inhibitor can be administered to a subject in the form of an administered therapeutic and/or as part of a genetic therapy. An “effective amount” is the amount of miRNA, artificial miRNA, Drosha protein or Drosha inhibitor necessary to result in a desired physiological change in the subject. The term “therapeutically effective amount” is the amount of miRNA, artificial miRNA, Drosha protein or Drosha inhibitor necessary to achieve a desired effect with respect to a disease or condition. The therapeutically effective amount can, but need not, cure the disease or condition. For example, the therapeutically effective amount can provide a partial benefit, such as alleviation or improvement of at least one symptom of the disease or condition.

In the context of cancers, therapeutically effective amounts can inhibit tumor growth, inhibit cancer cell proliferation, prevent metastasis, reduce the number of metastases, induce cancer cell death, induce apoptosis of cancer cells, inhibit angiogenesis near cancer cells, reduce cancer-associated pain, reduce relapse or re-occurrence, induce chemo- or radiosensitivity in cancer cells and/or prolong a subject's life.

For administration, effective amounts and therapeutically effective amounts (referred to herein as doses) can be initially be estimated based on results from in vitro assays and/or animal model studies. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC₅₀ as determined in cell culture. Such information can be used to more accurately determine useful doses in humans, veterinary animals (for example, dogs, cats and horses), livestock (for example, cattle, buffalo, sheep, pigs, goats, chickens), research animals (for example, monkeys, rats, mice, fish, flies and worms), other domesticated animals (for example, animals in zoos, circuses and aquariums including elephants, tigers, lions, sharks, rays and dolphins) and plants (all subjects herein).

The actual dosage amount administered to a particular subject can be determined by a physician, veterinarian or researcher taking into account parameters such as physical and physiological factors including body weight, severity of condition, type of disease, previous or concurrent therapeutic interventions, idiopathy of the subject and route of administration.

Useful doses often range from 0.1 to 5 mg/kg/day or from 0.5 to 1 mg/kg/day or from 0.1 to 5 μg/kg/day or from 0.5 to 1 μg/kg/day. In other non-limiting examples, a dose can comprise from 1 μg/kg/day, 5 μg/kg/day, 10 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 200 μg/kg/day, 350 μg/kg/day, 500 μg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day, 350 mg/kg/day, 500 mg/kg/day or 1000 mg/kg/day. Effective amounts and therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (days, weeks, months, etc.).

In certain embodiments, miRNA, artificial miRNA, Drosha protein, Drosha inducer or Drosha inhibitor are provided as part of pharmaceutical compositions. The pharmaceutical compositions can comprise, for example, at least 0.1% miRNA, artificial miRNA, Drosha protein or Drosha inhibitor. In other embodiments, the pharmaceutical composition can comprise between 2% to 75% of the weight of the unit, or between 25% to 60% of the weight of the unit miRNA, artificial miRNA, Drosha protein or Drosha inhibitor.

Pharmaceutical compositions can be formulated in any conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of miRNA, artificial miRNA, Drosha protein, Drosha inhibitor miRNA vectors, artificial miRNA vectors, Drosha protein vectors or Drosha inhibitor vectors (in the context of formulations, all hereafter collectively referred to as “the therapeutics”) into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

The therapeutics can be included within formulations for administration as free bases, neutral or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those that substantially retain the biologic activity of free bases. Pharmaceutically acceptable salts, include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine. Pharmaceutical salts tend to be more soluble in solvents than the corresponding free base forms.

The therapeutics can also be attached or conjugated to other chemical entities to increase cellular uptake. Exemplary chemical entities include acridine derivatives, 2-methoxy-6-chloro-9-aminoacridine, cross-linkers, psoralen derivatives, azidophenacyl, proflavin, azidoproflavin, metal complexes, EDTA-Fe(II), o-phenanthroline-Cu(I), porphyrin-Fe(II), alkylating moieties, endonucleases, artificial endonucleases, amino-1-hexanolstaphylococcal nuclease, alkaline phosphatase, terminal transferases, abzymes, cholesteryl moieties, lipophilic carriers, lipofectin, DOTMA, DOPE, DOTAP, peptide conjugates, long chain alcohols, phosphate esters, amino acids, mercapto groups, polylysine or other polyamines.

The therapeutics may particularly be administered in combination with a cationic amine such as poly (L-lysine) and/or may be conjugated to a chemical moiety, such as transferrin and/or cholesteryls. In particular embodiments, linking the therapeutics to a suitable array of mannose residues targets them to the liver.

In particular embodiments, the therapeutics can be introduced into cells by microinjection, electroporation, lipid transfection, liposome mediated transfection, calcium phosphate transfection, calcium phosphate precipitation, DEAE-dextran followed by polyethylene glycol, sonic loading, microprojectile bombardment, or agitation with silicon carbide fibers.

Certain aspects of the disclosure include contacting and introducing into a target cell a vector capable of expressing a pri-miRNA to regulate the expression of a target gene in the cell. The vector produces the pri-miRNA transcript, which is then processed into precursor microRNA in the cell, which is then processed to produce the mature functional miRNA which is capable of altering accumulation of a target protein in the target cell. Accumulation of the protein may be effected in a number of different ways. For instance the miRNA may directly or indirectly affect translation or may result in cleavage of the mRNA transcript or even effect stability of the protein being translated from the target mRNA. MiRNA may function through a number of different mechanisms. The methods and products of the disclosure are not limited to any one mechanism. The method may be performed in vitro, e.g., for studying gene function, ex vivo or in vivo, e.g. for therapeutic purposes.

The therapeutics can also be provided as pro-drugs. The term “prodrug” refers to a therapeutic that can undergo biotransformation (e.g., either spontaneous or enzymatic) within the subject to release, or to convert (e.g., enzymatically, mechanically, electromagnetically, etc.) an active or more active form of the therapeutic after administration. Prodrugs can be used to overcome issues associated with stability, toxicity, lack of specificity, or limited bioavailability and often offer advantages related to solubility, tissue compatibility, and/or delayed release (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drag Action, pp. 352-401, Academic Press, San Diego, Calif. (1992) both incorporated by reference for their teachings regarding the same).

For example, a subject can be provided an miRNA or artificial miRNA molecule corresponding to a particular miRNA by administering a nucleic acid molecule that functions as the corresponding miRNA once inside the cell. In these embodiments, the nucleic acid molecule is processed into the intended miRNA or artificial miRNA once it has access to the cell's miRNA processing machinery. In particular embodiments, the processing is post-translational modifications, such as, without limitation, adenosine to inosine editing.

Exemplary protein prodrugs can comprise an active protein and a chemical masking group (e.g., a group that reversibly suppresses the activity of the protein). Some preferred prodrugs are variations or derivatives of proteins that have sequences that are cleavable under metabolic conditions. Exemplary prodrugs become active or more active in vivo or in vitro when they undergo a biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation, etc.).

When the therapeutics are provided as part of a genetic therapy, “in vivo expression elements” are any regulatory nucleotide sequence, such as a promoter sequences or promoter-enhancer combinations, which facilitate the efficient expression of the therapeutic following administration to a subject. The in vivo expression element may, for example, be a mammalian or viral promoter, such as a constitutive or inducible promoter or a tissue specific promoter, examples of which are well known to one of ordinary skill in the art. Constitutive mammalian promoters include polymerase promoters as well as the promoters for the following genes: hypoxanthine phosphoribosyl transferase (HPTR), adenosine deaminase, pyruvate kinase, and beta-actin. Exemplary viral promoters which function constitutively in eukaryotic cells include promoters from the simian virus, papilloma virus, adenovirus, human immunodeficiency virus (HIV), Rous sarcoma virus, cytomegalovirus, the long terminal repeats (LTR) of moloney leukemia virus and other retroviruses, and the thymidine kinase promoter of herpes simplex virus. Other constitutive promoters are known to those of ordinary skill in the art. Inducible promoters are expressed in the presence of an inducing agent and include metal-inducible promoters and steroid-regulated promoters. For example, the metallothionein promoters is induced to promote transcription in the presence of certain metal ion. Other inducible promoters are known to those of ordinary skill in the art.

Examples of tissue-specific promoters include: for muscle and cardiac tissue, creatine kinase and alpha-actin promoter; for B cells, immunoglobulin heavy or light chain promoters; for liver, HMG-COA reductase promoter, sterol regulatory element 1, phosphoenol pyruvate carboxy kinase (PEPCK) promoter, human C-reactive protein (CRP) promoter, human glucokinase promoter, cholesterol 7-alpha hydroylase (CYP-7) promoter, beta-galactosidase alpha-2,6 sialyltransferase promoter, insulin-like growth factor binding protein (IGFBP-1) promoter, aldolase B promoter, human transferrin promoter, and collagen type I promoter; for prostate, prostatic acid phosphatase (PAP) promoter, prostatic secretory protein of 94 (PSP 94) promoter, prostate specific antigen complex promoter, and human glandular kallikrein gene promoter (hgt-1); for gastric tissue, human H+/K+-ATPase alpha subunit promoter; for pancreas, pancreatitis associated protein promoter (PAP), elastase 1 transcriptional enhancer, pancreas specific amylase, elastase enhancer promoter, and pancreatic cholesterol esterase gene promoter; for endometrium, uteroglobin promoter; for adrenal cells, cholesterol side-chain cleavage (SCC) promoter; for nervous system, gamma-gamma enolase (neuron-specific enolase, NSE) promoter; for brain, neurofilament heavy chain (NF-H) promoter; for lymphocytes, human CGL-1/granzyme B promoter, terminal deoxy transferase (TdT), lambda 5, VpreB, Ick (lymphocyte specific tyrosine protein kinase p561ck) promoter, the human CD2 promoter and its 3′ transcriptional enhancer, and the human NK and T cell specific activation (NKG5) promoter; for colon, pp60c-src tyrosine kinase promoter, organ-specific neoantigens (OSNs) promoter, and colon specific antigen-P promoter; for breast cells, human alpha-lactalbumin promoter; and for lung, cystic fibrosis transmembrane conductance regulator (CFTR) gene promoter. Other elements aiding specificity of expression in a tissue of interest can include secretion leader sequences, enhancers, nuclear localization signals, endosmolytic peptides, etc. In particular embodiments, these elements are derived from the tissue of interest to aid specificity.

VI. Formulations & Routes of Administration

Pharmaceutical compositions disclosed herein generally include pharmaceutically acceptable carriers which refer to compositions that do not produce significantly adverse, allergic or other untoward reactions that outweigh the therapeutic benefit of administration. Exemplary pharmaceutically acceptable carriers and formulations are disclosed in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, which is incorporated by reference herein for its teachings regarding the same. Moreover, for human administration, all formulations will meet sterility, pyrogenicity, general safety and purity standards as required by U.S. FDA Office of Biological Standards and/or other relevant foreign regulatory agencies.

Generally used pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., anti-oxidants, antibacterial agents, antifungal agents including parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof), isotonic agents, absorption delaying agents, salts, preservatives, stabilizers, gels, binders, disintegration agents, and lubricants. Except insofar as any conventional pharmaceutically acceptable carrier is incompatible with the particular therapeutic disclosed herein, its use in the pharmaceutical compositions is encompassed.

Formulations can be generated based on the chosen route of administration. Formulations can be administered by injection, inhalation, infusion, perfusion, lavage or ingestion. Routes of administration can include intravenous, intradermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, intraprostatic, intrapleural, intratracheal, intranasal, intravitreal, intravaginal, intrarectal, topically, intratumoral, intramuscular, intravesicular, intrapericardial, intraumbilical, intraocularal, subcutaneous, subconjunctival and/or mucosal.

For injection, formulations can be made as aqueous solutions, such as in buffers such as Hanks' solution, Ringer's solution, or physiological saline. The solutions can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the formulation can be in lyophilized and/or powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For topical administration formulations can be made as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

For nasal administration, formulations can be made as aqueous solutions designed to be administered to the nasal passages in drops or sprays. Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained. Thus, in preferred embodiments aqueous nasal solutions usually are isotonic or slightly buffered to maintain a pH of 5.5 to 6.5.

For transmucosal administration, formulations can be made with penetrants appropriate to the barrier to be permeated. Such penetrants are generally known in the art.

For oral administration, the formulations can be made as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like. For oral solid formulations such as, for example, powders, capsules and tablets, suitable excipients include binders (gum tragacanth, acacia, cornstarch, gelatin), fillers such as sugars, e.g. lactose, sucrose, mannitol and sorbitol; dicalcium phosphate, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents can be added, such as corn starch, potato starch, alginic acid, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms can be sugar-coated or enteric-coated using standard techniques. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc. can also be used.

For administration by inhalation, formulations can be made as aerosol sprays from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic and a suitable powder base such as lactose or starch.

Therapeutics can also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the therapeutic can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salts.

Additionally, therapeutics can be delivered using sustained-release systems, such as semipermeable matrices of solid polymers containing the therapeutic. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the therapeutic for a few weeks up to over 100 days.

Examples

Materials and Methods

Counting Method. Position 1 was assigned to the first nucleotide pair after the Drosha cutting site. The nucleotides that would form the single stranded overhang after Drosha processing were assigned negative positions (−1, −2 etc.) and if the cutting site was known for only one strand the overhang was assumed to be 2nt. Positions were then assigned for each nucleotide pair in ascending order moving towards the Dicer cleavage site. The average hairpin contains several mismatches, which occasionally contain more nucleotides in one strand than in the other. Whenever such a length discrepancy occurred, the shorter strand was used to assign the mismatch position, using the later position whenever an asymmetric mismatch was located between two positions. Each position where the nucleotides were bound to each other was assigned the score 0, while positions with at least one nucleotide mismatched were given the score 1.

Genomic location. Data from miRBase was used to determine whether each miRNA was intronic or intergenic. The fold change values in the two groups are visualized in FIG. 2. Significance was calculated using a t-test. Information regarding whether each miRNA was intronic or intergenic was retrieved from miRBase and fold change distribution was analyzed for each of the two groups and differences in distribution was calculated using a t-test.

miRNA machinery and structure in neuronal differentiation. H1 cells were differentiated into neurons using 90% confluent cells on Matrigel. The differentiation was performed using a modified version of the dual SMAD inhibition protocol (Chambers et al. 2009), using the TGF-β inhibitor SB432542, ALK inhibitor LDN193189, and cyclopamine in CDM Basal media, which was changed daily for 12 days. At time points 0, 6, and 12 days starting from the first addition of inhibitors, cells were harvested. mRNA and miRNA were purified using the RNeasy Plus Mini Kit, and the miRNeasy Mini Kit, respectively, according to manufacturer instructions (Qiagen). Expression levels were measured using RNAseq (Expression Analysis Inc) and single-color miRNA microarrays (LC Sciences) respectively. RNAseq expression data were then count- and length-normalized to transcripts per million (TPM) after exclusion of mitochondrial genes, and miRNA expression data were Lowess normalized for cross-chip comparisons.

H1 Cell Culture.

H1 human embryonic stem cell lines were cultured on a feeder layer (MEFs) in Dulbecco's modified Eagle's medium (DMEM)/Ham's F-12 medium containing GlutaMax supplemented with 20% serum replacer (SR), 1 mM sodium pyruvate, 0.1 mM non-essential amino acids, 50 U/ml penicillin, 50 ug/ml streptomycin, 0.1 mM β-mercapto-ethanol (Sigma-Aldrich, St. Louis), and 2 ng/ml basic fibroblast growth factor (Qi et al 2009). Knockdowns of Drosha and Dicer were generated by infection with lentiviral vectors containing shRNA constructs against Drosha and Dicer respectively. Control cells were infected with control viruses. After passaging the next day, infected cells were treated with blasticidin (0.5 ug/ul) for selection until discrete clusters of cells appeared. If cells showed less stability with respect to Drosha knockdown, cells were repeatedly selected with antibiotics (Qi et al. 2009).

Generation of HeLa line with Drosha knockdown. HeLa cells were transduced with a pL6-Tet lentiviral vector containing shRNA against Drosha (Qi et al. 2009) (Titer 1.79E+08, MOI of 1:10; 10 μg/ml blasticidin selection for 4 days). Generation of the control cells was done with a pLKO.1 control lentivirus, (MOI 1:10; 10 μg/ml puromycin selection for 4 days).

Drosha qPCR analysis. Drosha and DGCR8 levels were measured in Drosha KD and Control HeLa cells using the SYBR-GREEN Q-PCR kit. Drosha Ct values were normalized to GAPDH (ΔCt: Drosha-GAPDH). The ΔΔCt values were calculated by subtracting the Drosha ΔCt values in the Control cells from those values in the KD cells. Fold change was calculated using the (2̂(−ΔΔCt)) method.

Total RNA extraction and quantitative RT-PCR analysis. Brain and liver tissues were dissected from WT mice (n=3). Tissues were homogenized using mortar and pestle in a liquid nitrogen bath. RNA was extracted from cells adherent on plates or from tissue homogenate using Trizol reagent (Invitrogen) and cDNA was synthesized with the Omniscript RT kit (Qiagen). Beta-actin or UBC was used as endogenous control for normalization. Quantitative PCR reactions were performed in triplicate using the SyberGreen (Applied Biosystems) with the 7300 real time PCR system (Applied Biosystems). Primers used in our study are listed in the following Table 4.

TABLE 4
qPCR Primer Sequences.
Primer    Sequence
Drosha    SS-AGGAGTACGCCATAACCAACG
          AS-CAATCGTGGAAAGAAGCAGACA
β-actin   F-TCCCTGGAGAAGAGCTACG
          R-GTAGTTTCGTGGATGCCACA
Gapdh     SS-TGATGACATCAAGAAGCTGGTGAAG
          AS-TCCTTGGAGGCCATGTGGGCCAT
Bleomycin F-AGCTGTACGCCGAGTGGTC
          R-CGTGTCAGTCCTGCTCCTC
Ubc       F-ATTTGGGTCGCGGTTCTTG
          R-TGCCTTGACATTCTCGATGGT

Normalized Drosha levels in the brain were compared to those in the liver and the fold change was calculated using the 2″(−ΔΔCt) methods.

qPCR of miRNAs was conducted using TaqMan® miRNA assays (Applied Biosystems). miRNA expression was measured in both DroshaKD and Control HeLa cells. Raw Ct values for miRNAs were first normalized to RNU66 (endogenous snoRNA, internal control). Bleomycin values were normalized to GAPDH. To normalize to transfection efficiency, the normalized miRNA values were re-normalized to the normalized Bleomycin values (normalized miRNA ΔCt−normalized Bleomycin ΔCt). This new normalized value from control cells was subtracted from the corresponding value in the knockdown cells to generate the ΔΔCt values. Fold change with respect to the control cells was calculated using the 2̂(−ΔΔCt) method.

Protein extraction and Western blot. With the exception of mouse tissues, protein extraction and Western blot analysis followed procedures that were described previously (Zhou et al., 2011). Briefly, cells were washed with Dulbecco's PBS (Sigma Aldrich, St. Louis, Mo.) and directly lysed on culture dish using M-PER Mammalian Protein Extraction Reagent (Thermo Scientific, Rockford, Ill.; 0.5 ml per 35 mm plate) and protease inhibitor cocktail (Complete Mini, Roche Applied Science, Germany). 20 μg of protein extracts were loaded, separated by 4-20% SDS-PAGE using Mini-PROTEAN TGX Precast Gels (Bio-Rad, Hercules, Calif.), and transferred to polyvinylidene difluoride transfer membranes (Thermo Scientific). Membranes were blocked with 5% nonfat dry milk for at least 60 minutes at room temperature, and incubated overnight at 4° C. with primary antibody. Blots were incubated for one hour with horseradish peroxidase-conjugated Blotting Grade Affinity Purified secondary antibodies (Bio-Rad) and were visualized by enhanced chemiluminescence (Millipore Corp, Billerica, Mass.). Protein expression levels in the gel were quantified by densitometry implemented in Image-J (National Institutes of Health, Bethesda http://rsb.info.nih.gov/ij/, 1997-2013). Antibodies used in this study are: rabbit anti-Drosha antibody (Cell Signaling Technology, Beverly, Mass.) diluted at 1:1000, mouse anti-β-actin antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.) diluted at 1:5000, goat anti-rabbit antibody (Bio-Rad Laboratories, Hercules, Calif.) diluted at 1:10000 and goat anti-mouse antibody (Bio-Rad Laboratories, Hercules, Calif.). For mouse tissues, the protocol above was followed for protein extraction, gel loading, and the quantification of Drosha expression. As a control, either Western using actin Ab or Coomassie Brilliant Blue R (Sigma Aldrich) staining was used. Entire-cell protein expression was quantified using Image-J.

Transfections. The mutations were performed on the passenger strand, leaving the mature strand unchanged in order to be able to detect both the mutated and non-mutated miRNAs using the same TaqMan® assay. The pri-miRNA inserts were amplified from genomic DNA by PCR, including the hairpin and -200nt flanks on each side. The inserts were ligated into a modified pcDNA3.1+ plasmid with the neomycin selection marker replaced with a bleomycin resistance gene. Mutated versions of the constructs, with altered mismatches in the 9-12 region, were ordered from Genscript. The miRNA constructs were transiently transfected into HeLa cells using Lipofectamine2000. RNA was extracted after 48 hours using Trizol.

Analysis of Drosha and miRNA expression in mouse tissues. For GDS3052 and GDS3142: These are two microarray analyses done in mouse using an Affymetrix Mouse Genome 430 2.0 chip. Drosha expression values were extracted from the datasets and were normalized to a gene that in both studies showed minimal variation between tissues; Eef2 (eukaryotic translation elongation factor 2). Drosha expression was represented as percent of Eef2 in the tissues.

For Takada et al. 2006: The miRNAs expressed in each tissue were first sorted according to number of clones (highest number of clones being highest expression and lowest number of clones being lowest expression). The miRNAs were then divided into groups based on the number of mismatches in the 5, 9-12 region (X-axis) and within each group the average expression level (Y-axis) was calculated by geometric mean.

In vitro processing of miRNAs. Plasmids for wild type (wt) and modified versions of mir-137 and mir-200b were linearized, gel purified and in vitro transcribed using the Riboprobe (Promega) protocol and labeled with α³²P-CTP. Transcripts were purified using the RNAeasy mini kit (Qiagen) and then allowed to fold by addition of KAc, heating to 95° C. for 5 min and then kept on ice till the processing reaction. Processing was performed by mixing folded pri-microRNA transcripts with 8 μg 293T cell nuclear extract (Protein One) for 10, 30 and 90 minutes at 37° C. followed by trizol extraction and run on a 10% polyacrylamide-urea gel for 4 hours at 650V. Gel exposures were quantified using ImageJ64 software where intensities of bands corresponding to pre-miRNAs were normalized to regions containing pri-miRNA transcripts.

Statistical analysis. Throughout the experiments, P values for expression levels were calculated using Student's t-test. *, P<0.05; and **, P<0.01. Bars show Standard error of the mean (SEM) for at least 3 separate experiments. P-values for differences in mismatch trends were calculated in R using a chi-square test with Yates continuity correction.

Results

Differences in change of miRNA expression due to Drosha knockdown in hESC (H1) correlate with differences in predicted pri-miRNA secondary structures. Previous research in the laboratory used H1 human embryonic stem cells with Drosha KD to study the response to a general decrease of miRNAs in stem cells (Bar et al. 2008; Qi et al. 2009; Stadler et al. 2010). qPCR of 220 microRNAs in Drosha KD hESCs showed a general decrease of miRNA expression. However, a group of miRNAs was still processed efficiently, despite the 3-fold reduction of Drosha expression (FIG. 1). It seems logical that mirtrons (which bypass Drosha processing) would be unaffected by Drosha KD, however, few mirtrons are known (Berezikov et al. 2007) and none of the known mirtrons are in the 220 miRNAs assayed by qPCR. Mirtrons are generally located within small introns, but no statistically significant correlation could be verified between genomic location and fold change of miRNA expression (p=0.27); the mean fold change was 2.8 for intergenic miRNAs, and 2.4 for the intronic miRNAs (FIG. 2).

Given that bulges in the stem of RNA hairpins seem to prevent processing by the miRNA pathway in general, and that others have shown Drosha to differentially process miRNAs based on structural features (Han et al. 2006; Ritchie et al. 2007; Feng et al. 2011), it seems logical that differences in the number of mismatches in miRNA hairpins would alter their interaction with the Microprocessor, and could explain the variation of fold change in response to Drosha KD. In order to compare the three-dimensional shape of the pri-miRNAs in the described dataset, a novel method of assigning position within the miRNA hairpin was developed in order to give a better representation of the mismatch locations relative to each other and the Drosha cutting site in three dimensional space (FIG. 3A). Position assignment and mismatch counting was performed by defining the location of each mismatch in terms of distance from the Drosha cutting site using predicted secondary structure, counting asymmetric mismatches as the length of the shorter strand; this is different from previously described methods to calculate mismatch positions in pri-miRNAs, where asymmetry was not taken into account (Han et al. 2006).

The secondary structures for the 220 miRNAs from the H1 dataset were calculated using the ViennaRNA package (Hofacker et al. 1994), and exact locations of cutting sites were found through miRBase. The dataset contained 220 miRNAs, and 202 were selected by sorting out any miRNAs with ambiguous secondary structure predictions. The dataset was split in half based on fold change (FIG. 1, arrow), and the sums of mismatches at each nucleotide position were compared between the two groups. The summation revealed that miRNAs with a high fold change when Drosha levels were reduced had more mismatches in position(s) 5 and 10-12 than miRNAs with low fold change, and that these differences were statistically significant (FIG. 3B, C). A knockdown of Dicer did not result in the same trend (FIG. 10) In addition p-values were calculated for the quartiles at the extreme ends of the DroshaKD dataset, with a sample size extrapolated to that of the total data set (FIG. 3C). For subsequent experiments and analysis position 9 was also included because it follows the same trend as positions 10-12. This takes into account any lack of specificity in the method of assigning positions.

Correlation of Drosha expression and miRNA secondary structure profile in mature tissues. Having shown that pri-miRNA processing by Drosha is affected by the pri-miRNA secondary structure in cell culture whether this mechanism is used in vivo as a mechanism to selectively regulate groups of miRNAs based on secondary structure was also investigated. Because Drosha expression alters the expression of miRNAs with bulges in the central region more than miRNAs without (FIG. 3), and because of the crucial role of miRNAs for cellular biology, whether or not Drosha expression levels vary across cell type or according to developmental stage in mammals was examined. To find naturally occurring examples of Drosha variation, the Gene Expression Omnibus (GEO) was used to find microarray data of relevant gene expression in mature and differentiating mouse tissues.

From the GEO expression datasets GDS3052 and -3142, expression data for Drosha and common housekeeping genes in multiple mouse tissues was extracted and analyzed. In both datasets the expression of Drosha is dramatically lower in liver and submaxillary/salivary gland (4-10 fold) than in brain tissues when normalized to EEF2 (FIG. 4A-B). To test whether the difference in Drosha expression was dependent on the housekeeping gene used for normalization, the fold change of expression between liver and brain tissues for five housekeeping genes; EEF2, RPL13A, SDHA, TBP, and UBC was analyzed. The data revealed that the expression change for Drosha is greater than variation among known housekeeping genes (FIG. 4C-D), showing that Drosha is differentially expressed regardless of the housekeeping gene used for normalization.

The differential expression of Drosha in mouse brain and liver by qPCR was validated, and normalized to UBC, verifying that Drosha expression was 5.6 fold higher in the brain than in the liver (FIG. 4E; n=3, p<0.01). Furthermore, Western blotting revealed 9.6 or 3.2 fold higher Drosha protein expression in brain than in liver when normalized to total protein or to β-actin expression, respectively (Coomassie Blue staining or to β-actin Western; FIG. 4F,G; FIG. 11).

Having validated that Drosha levels are higher in brain than in liver, whether miRNA expression varies according to the number of mismatches in the 9-12nt region of the miRNAs in the two tissues was examined. miRNA expression data from mouse brain and liver (Takada et al. 2006) was analyzed. It was found that miRNAs with mismatches in positions 5 and 9-12 are enriched in brain but not in liver and that the difference was larger the more mismatches present (FIG. 4H), supporting the hypothesis that miRNAs with central mismatches are not processed efficiently when Drosha is limiting. This trend for miRNA expression did not correlate with mismatches in the other positions (FIG. 12).

Coordination of Drosha and miRNA expression by microRNA secondary structure during T-cell development and neuronal differentiation. Because Drosha levels vary between mature tissue types and expression levels of miRNAs with mismatches in the central region are high relative to rigid miRNAs when Drosha levels are high, whether this mechanism is used to dynamically alter the miRNA expression profiles during cell development was tested. In order to establish this relationship, Drosha expression levels during T-cell differentiation was determined and a 3-fold decrease in Drosha expression from double-negative T-cells (DN3) to CD4+ cells (Chong et al. 2010) (FIG. 5A) was found. In neuronal lineage, Drosha and Eef2 expression were compared during the proliferation of mouse neural progenitors (GDS3442). A significant decrease (p<0.01) in Drosha expression as the cells proliferate and mature in embryonic mouse brains was observed (FIG. 5B).

Whether the miRNA groups correlate with the Drosha levels was tested. It was found that the lower Drosha expression in CD4+ compared to DN3 cells correlates with lower expression of miRNAs with 5 mismatches in the region 5, 9-12nt from the Drosha cutting site and the ratio of expression between DN3 and CD4+ for miRNAs grouped by the number of mismatches in positions 5 and 9-12 shows that the difference in Drosha expression between DN3 and CD4+ cells correlates with a decrease in miRNA expression based on number of mismatches (FIG. 5C). In DN3 cells Drosha levels are relatively high, and mismatched miRNAs are highly expressed; in CD4+ cells Drosha levels are low, and predominantly rigid miRNAs are produced. This agrees with previous results that when Drosha levels are low the levels of mature miRNAs generated from mismatched hairpins go down disproportionately compared to rigid miRNAs (FIG. 3B-C, 4C-D). Mismatch counting of the complete hairpin, to control for the difference being local to the 5, 9-12 region, did not result in a similar trend (FIG. 13).

Drosha levels in hESC derived neuronal differentiation process were also determined. RNAseq data from early neuronal differentiation of H1 hESC shows an increase in Drosha, with a greater change occurring over day 0 to day 6 than day 6 to day 12 (FIG. 6A). Canonical and non-canonical components of the miRNA biogenesis pathway have a significantly greater change in expression between days 0 and 6 than between days 6 and 12 of the neural differentiation protocol. miRNA microarray data from the same period, day 0 to day 6, when Drosha levels increase, shows that the miRNAs with positive fold-change have significantly more mismatches in the region(s) 5, 9-12 than miRNAs with negative fold change (FIG. 6B). Between days 6 and 12, when changes in Drosha expression are significantly lower, no significant difference in number of mismatches can be found between miRNAs grouped by fold-change (FIG. 6C). This shows that when Drosha levels increase in early neuronal differentiation the expression of miRNAs generated from hairpins with mismatches in the 5, 9-12 region go up relative to more rigid hairpins, and when Drosha levels stabilize mismatched miRNAs no longer behave differently from rigid ones (FIG. 6B-C). Whether increasing or decreasing during cell development, changes in Drosha levels affect groups of miRNAs based on their secondary structure. To control for the difference being local to the 5, 9-12 region, mismatches were counted in the remaining positions for a subset of 166 miRNAs, where no similar trend was observed (FIG. 14).

Biochemical validation of the relationship between pri-miRNA secondary structure, miRNA expression, and Drosha expression in vivo. Given the spatial and developmental heterogeneity of Drosha expression and its' correlation with miRNA expression based on secondary structure (FIG. 3-6), it was hypothesized that mismatches in a miRNA hairpin approximately 9-12nt from the Drosha cutting site would confer increased sensitivity to low levels of Drosha. Conversely, the absence of mismatches would confer decreased sensitivity to Drosha expression. In order to test this hypothesis, the relative over expression of four miRNAs in two HeLa cell lines were compared; one with a stable Drosha knockdown, the other transduced with a control virus (Control). Drosha protein levels were significantly reduced in the KD line (5-fold reduction; FIG. 12) resulting in downregulation of endogenous miRNAs (FIG. 15). miR-145 and miR-200b were selected for over-expression in these cells due to the clear presence of mismatches 9-12 nt from the Drosha cutting site (FIG. 7A-B), making them ideal candidates to represent miRNAs at one end of the spectrum with regards to secondary structure. For the same reason, miR-137 and miR-9-1 were selected due to the clear absence of mismatches 9-12 nt from the Drosha cutting site (FIG. 7C-D). Modifications of the 9-12nt region were designed to either insert or remove mismatches without disrupting the rest of the hairpin, while preserving the primary sequence of the mature miRNA, changing each miRNA from one extreme structure to the other while allowing for detection by traditional methods (FIG. 7A-D). Because alteration of the secondary structure close to the Drosha cutting site has previously been shown to completely disrupt processing and may affect strand selection during RISC loading, this region was not modified. (Zeng and Cullen 2003; Noland et al. 2011) Fold change of miRNA over expression (KD/ctrl; referred to as “relative over expression”) was measured by qPCR to determine whether or not mismatches in the central region determine sensitivity to Drosha in vivo.

For miR-145, mutation from a semi-rigid to a rigid stem increased relative over expression by 1.52-fold, p<0.01 (FIG. 8A). For miR-137, mutation from a rigid stem to a less rigid stem decreased relative over expression by 3.84-fold, p<0.05 (FIG. 8B). For miR-200b, mutation from a quasi-rigid to a more rigid stem increased relative over-expression by 3.76-fold, p=0.05 (FIG. 8C). For miR-9-1, mutation to create mismatches in the 9-12nt region decreased relative over-expression by 4.66-fold (FIG. 8D). These data show that the addition or removal of mismatches did affect the level of miRNA overexpression in DroshaKD/Control, with more mismatches generating a lower ratio than the corresponding miRNA without mismatches 9-12nt from the Drosha cutting site.

In vitro processing of modified miRNAs. Having shown the differential processing of rigid and mismatched miRNAs in vivo, this relationship was tested in vitro. Linearized plasmids containing wild type (wt) and modified versions of mir-137 (203nt) and mir-200b (430nt) were in vitro transcribed and radiolabeled, followed by Drosha processing for 10, 30 and 90 minutes using nuclear extract from 293T cells. The resulting RNA was purified and visualized on a 10% urea-polyacrylamide gel (FIG. 9A). Intensities of the bands corresponding to the pre-miRNA were quantified and normalized to the intensities of the regions containing pri-miRNA. Negative controls using only protein buffer and no lysate showed no detection in the bands used to quantify pre-miRNAs. Calculation of expression ratios of normalized 10 min and 90 min samples showed a consistently higher ratio for more rigid miRNAs than for their more mismatched counterparts (FIG. 9B). While the fold changes are smaller in in vitro assay compared to in vivo experiments (compare FIG. 8B-C to FIG. 9), the trend is the same, consistently showing that mismatched miRNAs have a higher sensitivity to reduced Drosha activity.

Discussion

It has been shown that when Drosha levels change, the change in expression levels of miRNAs with mismatches in the hairpin, 9-12nt from the Drosha cutting site is greater than the change in expression levels of miRNAs that lack mismatches in the same region. This correlation was found in mature mouse tissues and during development. The sensitivity to changes in Drosha expression for miRNAs was also achieved by changing their secondary structure. These data suggest that secondary structure of miRNA affects miRNA's processing efficiency when Drosha is limiting and that differentiating cells may use this as a means of miRNA regulation.

Previous work on standardizing the miRNA secondary structure and cataloguing mismatch locations has used the approach of assigning mismatch positions for each strand of the hairpin separately (Han et al. 2006). In order to improve the representation of mismatch locations in three dimensional space, a mismatch mapping technique was developed that takes both strands into consideration simultaneously in the analysis. This counting method resulted in a very consistent measurement of 21nt between the Drosha and Dicer cutting sites, which is consistent with previous reports indicating that Dicer processing of pre-miRNAs with asymmetric mismatches seems to explain the heterogeneity of length observed amongst mature miRNAs, and is also consistent with the idea that Dicer processing utilizes ‘molecular rulers’ which are size invariant (Starega-Roslan et al. 2010), which indicates that the developed counting method provides a good representation of the shape of the miRNA.

A relationship between secondary structure and pri-miRNA processing is well established, but no previous studies have focused specifically on the 9-12nt region within the pre-miRNA portion of the pri-miRNA and processing. pri-miRNAs are generally shorter, have fewer bulges and internal loops, and overall less mismatched bases within the stem region than non-miRNA-generating RNA transcripts, implying that secondary structure prediction is a reliable predictor of Drosha and Dicer processing (Ritchie et al. 2007). Furthermore, the secondary structure of pri-miRNAs controls the specificity and efficiency of Drosha processing, in vitro and in vivo, suggesting that Drosha substrate specificity may act as a mechanism for global regulation of miRNA expression profiles (Feng et al. 2011). On the other hand, it has also been shown that polymorphisms in pri-miRNA secondary structure do not affect processing (Diederichs and Haber 2006), but only one of the examined single nucleotide polymorphisms (SNPs) was within the pre-miRNA portion of the pri-miRNA structure. In a wider search of human miRNA genes, it was determined that SNPs did affect the processing and function of miRNAs and most of these SNPs were found between the Dicer and Drosha cutting sites (Sun et al. 2009). The results presented herein could explain the significance of SNPs outside the seed region, but within the pre-miRNA structure, of some cancer and disease related miRNAs, such as the mutation in the stem of hsa-mir-125a (Duan et al. 2007), or in miR-181b-2, miR-208, miR-520e (Wu et al. 2008).

The miRNA biogenesis is regulated on multiple levels. The transcription of primary miRNAs (pri-miRNA) is regulated by common transcription factors, e.g. c-Myc (Abdelmohsen et al. 2012), and some miRNAs are also found to be subject to methylation (Brueckner et al. 2007). miRNAs are transcribed in the nucleus by RNA polymerase II or III (Borchert et al. 2006; Kim and Nam 2006) as part of the pri-miRNA, whose length is highly variable, ranging from ˜200 up to several thousand nucleotides (Du and Zamore 2005; Cullen 2006). Drosha and DGCR8 bind the pri-miRNA, and Drosha cleaves pri-miRNAs at the base of the stem-loop and liberates a structure known as the precursor microRNA (pre-miRNA), which is ˜60-70 nucleotides in length and forms a frequently mismatched hairpin structure with a 2 nucleotide 3′ overhang (Basyuk et al. 2003; Lee et al. 2003; Ritchie et al. 2007). The DGCR8 mRNA has stem loop structures that can be cleaved by the Microprocessor, accordingly giving the Microprocessor a self regulating mechanism (Han et al. 2009). The pre-miRNA is transported from the nucleus to the cytoplasm by Exportin-5 and is subsequently cleaved by the enzyme Dicer with its cofactor trans-activator RNA (tar)-binding protein (TRBP) (Chendrimada et al. 2005), with a notable exception in mir-451, which bypasses Dicer cleavage and is processed by Ago instead (Cheloufi et al. 2010). Dicer cleavage is further regulated by Lin28, which binds to pre-miRNAs from the let-7 family (Nam et al. 2011). Dicer acts by binding the 3′-overhang and cleaves the pri-miRNA ˜22nt from the Drosha-cutting site to remove the terminal loop, resulting in an imperfect ˜22nt called miRNA:miRNA* (Hutvagner et al. 2001; Bernstein and Allis 2005; Feng et al. 2012). The miRNA enters the RNA-induced silencing complex (RISC), and the miRNA* is degraded, in a process where strand selection is variable (Bartel 2004; Du and Zamore 2005; Cullen 2006; Kim and Nam 2006). Although several mechanisms have been identified by which expression levels of select miRNAs are affected, and though Drosha is known to regulate overall Drosha expression, it has never previously been shown that the cell selectively can change miRNA expression profiles by altering levels of Drosha expression.

The current disclosure shows that Drosha levels vary between tissues and throughout cellular development, and that miRNAs without mismatches in the 9-12nt region are overrepresented in cells with low levels of Drosha, while highly mismatched miRNAs are highly expressed in cells with high levels of Drosha, and that this behavior can be altered by changing the miRNA secondary structure. This supports the hypothesis that the cell selectively regulates more rigid and more mismatched miRNAs by altering Drosha expression. This mechanism contributes to the phenotypic relevance of specific levels of Drosha expression in development and terminal differentiation. In addition to other examples of post-transcriptional regulation, this can explain why some polycistronic miRNAs that are driven by the same promoter have very different expression levels, and the impact of SNPs, as stated above. This mechanism may be utilized while designing artificial miRNAs to increase stability, control expression levels throughout differentiation, or fine-tune miRNA expression in different tissue types.

As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. As used herein, the transition term “comprise” or “comprises” means includes, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient or component not specified. The transition phrase “consisting essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment. As used herein, a material effect would result in an RNA that remains relatively unaffected by Drosha regulation when compared to an RNA with a different number of mis-matches in positions 5 and 9-12 from the Drosha cutting site.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.

In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and/or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the following examples or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 3rd Edition or a dictionary known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004).

REFERENCES

• Abdelmohsen K, Srikantan S, Kang M J, Gorospe M. 2012. Regulation of senescence by microRNA biogenesis factors. Ageing Res Rev 11(4): 491-500.
• Anokye-Danso F, Trivedi C M, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber P J, Epstein J A et al. 2011. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8(4): 376-388.
• Bar M, Wyman S K, Fritz B R, Qi J, Garg K S, Parkin R K, Kroh E M, Bendoraite A, Mitchell P S, Nelson A M et al. 2008. MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries. Stem Cells 26(10): 2496-2505.
• Bartel D P. 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2): 281-297.
• Basyuk E, Suavet F, Doglio A, Bordonne R, Bertrand E. 2003. Human let-7 stem-loop precursors harbor features of RNase III cleavage products. Nucleic Acids Res 31(22): 6593-6597.
• Berezikov E, Chung W J, Willis J, Cuppen E, Lai E C. 2007. Mammalian mirtron genes. Mol Cell 28(2): 328-336.
• Bernstein E, Allis C D. 2005. RNA meets chromatin. Genes Dev 19(14): 1635-1655.
• Borchert G M, Lanier W, Davidson B L. 2006. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13(12): 1097-1101.
• Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, Sultmann H, Lyko F. 2007. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 67(4): 1419-1423.
• Chambers S M, Fasano C A, Papapetrou E P, Tomishima M, Sadelain M, Studer L. 2009. Highly efficient neural conversion of human E S and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3): 275-280.
• Cheloufi S, Dos Santos C O, Chong M M, Hannon G J. 2010. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465(7298): 584-589.
• Chendrimada T P, Gregory R I, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R. 2005. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436(7051): 740-744.
• Chong M M, Zhang G, Cheloufi S, Neubert T A, Hannon G J, Littman D R. 2010. Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev 24(17): 1951-1960.
• Cullen B R. 2006. Viruses and microRNAs. Nat Genet 38 Suppl: S25-30.
• Davis B N, Hata A. 2009. Regulation of MicroRNA Biogenesis: A miRiad of mechanisms. Cell Commun Signal 7: 18.
• Davis B N, Hilyard A C, Lagna G, Hata A. 2008. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454(7200): 56-61.
• Diederichs S, Haber D A. 2006. Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing. Cancer Res 66(12): 6097-6104.
• Du T, Zamore P D. 2005. microPrimer: the biogenesis and function of microRNA. Development 132(21): 4645-4652.
• Duan R, Pak C, Jin P. 2007. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16(9): 1124-1131.
• Feng Y, Zhang X, Graves P, Zeng Y. 2012. A comprehensive analysis of precursor microRNA cleavage by human Dicer. RNA 18(11): 2083-2092.
• Feng Y, Zhang X, Song Q, Li T, Zeng Y. 2011. Drosha processing controls the specificity and efficiency of global microRNA expression. Biochim Biophys Acta 1809(11-12): 700-707.
• Fukuda T, Yamagata K, Fujiyama S, Matsumoto T, Koshida I, Yoshimura K, Mihara M, Naitou M, Endoh H, Nakamura T et al. 2007. DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat Cell Biol 9(5): 604-611.
• Gregory R I, Yan K P, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R. 2004. The Microprocessor complex mediates the genesis of microRNAs. Nature 432(7014): 235-240.
• Griffiths-Jones S, Grocock R J, van Dongen S, Bateman A, Enright A J. 2006. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34(Database issue): D140-144.
• Han J, Lee Y, Yeom K H, Nam J W, Heo I, Rhee J K, Sohn S Y, Cho Y, Zhang B T, Kim V N. 2006. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125(5): 887-901.
• Han J, Pedersen J S, Kwon S C, Belair C D, Kim Y K, Yeom K H, Yang W Y, Haussler D, Blelloch R, Kim V N. 2009. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136(1): 75-84.
• Hatfield S D, Shcherbata H R, Fischer K A, Nakahara K, Carthew R W, Ruohola-Baker H. 2005. Stem cell division is regulated by the microRNA pathway. Nature 435(7044): 974-978.
• Hofacker I L, Fontana W, Stadler P F, Bonhoeffer L S, Tacker M, Schuster P. 1994. Fast folding and comparison of RNA secondary structures. Monatsh Chem 125: 167-188.
• Hutvagner G, McLachlan J, Pasquinelli A E, Balint E, Tuschl T, Zamore P D. 2001. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293(5531): 834-838.
• Kim V N, Nam J W. 2006. Genomics of microRNA. Trends Genet 22(3): 165-173.
• Kuehbacher A, Urbich C, Zeiher A M, Dimmeler S. 2007. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 101(1): 59-68.
• Kuppusamy K T, Sperber H, Ruohola-Baker H. 2013. MicroRNA Regulation and role in stem cell maintenance, cardiac differentiation and hypertrophy. Curr Mol Med Submitted.
• Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. 2001. Identification of novel genes coding for small expressed RNAs. Science 294(5543): 853-858.
• Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S et al. 2003. The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956): 415-419.
• Mattick J S, Makunin I V. 2006. Non-coding RNA. Hum Mol Genet 15 Spec No 1: R17-29.
• Nam Y, Chen C, Gregory R I, Chou J J, Sliz P. 2011. Molecular basis for interaction of let-7 microRNAs with Lin28. Cell 147(5): 1080-1091.
• Noland C L, Ma E, Doudna J A. 2011. siRNA repositioning for guide strand selection by human Dicer complexes. Mol Cell 43(1): 110-121.
• O'Donnell K A, Wentzel E A, Zeller K I, Dang C V, Mendell J T. 2005. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043): 839-843.
• Qi J, Yu J Y, Shcherbata H R, Mathieu J, Wang A J, Seal S, Zhou W, Stadler B M, Bourgin D, Wang L et al. 2009. microRNAs regulate human embryonic stem cell division. Cell Cycle 8(22): 3729-3741.
• Ritchie W, Legendre M, Gautheret D. 2007. RNA stem-loops: to be or not to be cleaved by RNAse III. RNA 13(4): 457-462.
• Ruby J G, Jan C H, Bartel D R 2007. Intronic microRNA precursors that bypass Drosha processing. Nature 448(7149): 83-86.
• Shcherbata H R, Hatfield S, Ward E J, Reynolds S, Fischer K A, Ruohola-Baker H. 2006. The MicroRNA pathway plays a regulatory role in stem cell division. Cell Cycle 5(2): 172-175.
• Stadler B, lvanovska I, Mehta K, Song S, Nelson A, Tan Y, Mathieu J, Darby C, Blau C A, Ware C et al. 2010. Characterization of microRNAs involved in embryonic stem cell states. Stem Cells Dev 19(7): 935-950.
• Stadler B M, Ruohola-Baker H. 2008. Small RNAs: keeping stem cells in line. Cell 132(4): 563-566.
• Starega-Roslan J, Krol J, Koscianska E, Kozlowski P, Szlachcic W J, Sobczak K, Krzyzosiak W J. 2010. Structural basis of microRNA length variety. Nucleic Acids Res 39(1): 257-268.
• Stark A, Brennecke J, Bushati N, Russell R B, Cohen S M. 2005. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123(6): 1133-1146.
• Sun G, Yan J, Noltner K, Feng J, Li H, Sarkis D A, Sommer S S, Rossi J J. 2009. SNPs in human miRNA genes affect biogenesis and function. RNA 15(9): 1640-1651.
• Takada S, Berezikov E, Yamashita Y, Lagos-Quintana M, Kloosterman W P, Enomoto M, Hatanaka H, Fujiwara S, Watanabe H, Soda M et al. 2006. Mouse microRNA profiles determined with a new and sensitive cloning method. Nucleic Acids Res 34(17): e115.
• Wu M, Jolicoeur N, Li Z, Zhang L, Fortin Y, L'Abbe D, Yu Z, Shen S H. 2008. Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs. Carcinogenesis 29(9): 1710-1716.
• Zeng Y, Cullen B R. 2003. Sequence requirements for micro RNA processing and function in human cells. RNA 9(1): 112-123.
• Zeng Y, Yi R, Cullen B R. 2005. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J 24(1): 138-148.
• Zisoulis D G, Kai Z S, Chang R K, Pasquinelli A E. 2012. Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature 486(7404): 541-544.

Claims

1. An expression vector encoding an endogenous RNA-based molecule altered to encode at least one mis-match at nucleotide position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

2. An expression vector of claim 1 altered to encode two mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

3. An expression vector of claim 1 altered to encode three mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

4. An expression vector of claim 1 altered to encode four mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

5. An expression vector of claim 1 altered to encode five mis-matches at nucleotide positions 5, 9, 10, 11 and 12 from the RNA's Drosha cutting site.

6. An RNA-based molecule comprising an endogenous RNA sequence altered to include at least one mis-match at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

7. An RNA-based molecule of claim 6 altered to include at least two mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

8. An RNA-based molecule of claim 6 altered to include at least three mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

9. An RNA-based molecule of claim 6 altered to include at least four mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site.

10. An RNA-based molecule of claim 6 altered to include five mis-matches at position 5, 9, 10, 11 and 12 from the RNA's Drosha cutting site.

11. An RNA-based molecule of claim 6, wherein the RNA is miRNA.

12. A method of selectively targeting a tissue or cell type with high Drosha expression levels for up-regulation of an RNA molecule comprising administering an RNA-based molecule of claim 6 to a subject.

13. A method of claim 12 wherein the selective targeting results in a higher level of the up-regulated RNA molecule in liver over brain; in intestine over liver and pancreas; in ovaries over uterus; malignant cells over non-malignant cells or in young T-cells over mature T-cells.