NSF Award
1514600
Most genes in mammals are expressed from copies inherited from both the mother and the father, but a small number of genes are only expressed from one of these two copies; these are called imprinted genes. This project aims to investigate the mechanisms that ultimately allow one copy of these imprinted genes to be expressed while the other copy remains silent, or non-functional. Understanding the regulation of these genes is important because normal patterns of mammalian growth and development are perturbed if the expression of imprinted genes is dysregulated, as when both or neither copy is expressed. These studies will be conducted at Bryn Mawr College, a women's undergraduate institution, and will provide a diverse cohort of undergraduate students with an enhanced educational environment by affording them the opportunity to use current methodologies to advance scientific exploration, ultimately preparing these undergraduate women to be the next generation of research scientists.<br/><br/>Imprinted genes are only expressed from one of the two parentally inherited alleles. Monoallelic expression of imprinted genes is associated with differential DNA methylation on the maternal and paternal alleles that are passed to offspring at fertilization. What remains unknown is how further refinement of chromatin structure is achieved during post-fertilization development in order to maintain imprinted expression and establish tissue-specific imprinting. Post-fertilization acquisition of DNA methylation at additional sites within imprinted loci has been proposed to serve this purpose, but DNA methylation at such secondary differentially methylated regions is highly variable. This research will test the hypotheses that the observed variability is due to increased levels of hemi-methylation and/or increased levels of 5-hydroxymethylcytosine. In addition, this work will identify cis-regulatory elements responsible for tissue-specific imprinting using chromosome conformation capture to understand how these elements work in concert with epigenetic factors to achieve monoallelic vs. biallelic expression. Overall, this research will lend insight into the mechanisms governing the establishment and maintenance of chromatin structure critical for imprinted gene expression.
