Claims
- 1. A method for inducing insulin gene expression in cells, the method comprising the steps of:
(i) providing a cell that expresses a PDX-1 polynucleotide; and (ii) contacting the cell with a histone deacetylase inhibitor, thereby inducing insulin gene expression in the cells.
- 2. The method of claim 1, wherein the contacting step results in an induction of insulin expression at least two-fold compared to a cell not contacted by the histone deacetylase inhibitor.
- 3. The method of claim 1, wherein the cell further expresses a heterologous PDX-1 polynucleotide.
- 4. The method of claim 1, wherein the cell expresses a NeuroD polynucleotide.
- 5. The method of claim 4, wherein the cell expresses a heterologous NeuroD polynucelotide.
- 6. The method of claim 1, wherein the cell is a pancreatic β-cell.
- 7. The method of claim 6, wherein the β-cells are human β-cells.
- 8. The method of claim 1, wherein the cell produces a detectable amount of insulin prior to contacting the cell with the histone deacetylase inhibitor.
- 9. The method of claim 1, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.
- 10. The method of claim 1, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline
- 11. The method of claim 1, further comprising contacting the cells with a GLP-1 receptor agonist.
- 12. The method of claim 11, wherein the GLP-1 receptor agonist is a GLP-1 analog.
- 13. The method of claim 11, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.
- 14. The method of claim 13, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.
- 15. The method of claim 1, wherein the cells express a recombinant oncogene.
- 16. The method of claim 15, wherein the cells express more than one recombinant oncogene.
- 17. The method of claim 1, wherein the cells express a recombinant telomerase gene.
- 18. A method of identifying a compound that modulates β-cell function, the method comprising the steps of contacting a cell with a compound in the presence of a histone deactylase inhibitor, wherein the cell expresses a PDX-1 polynucleotide; and
determining the effect of the compound on β-cell function.
- 19. The method of claim 18, wherein β-cell function comprises insulin expression.
- 20. The method of claim 18, wherein insulin expression increases when the cell is contacted with the compound.
- 21. The method of claim 18, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.
- 22. The method of claim 18, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline
- 23. The method of claim 18, wherein the β-cell expresses a NeuroD/BETA2 polynucleotide.
- 24. The method of claim 18, further comprising contacting the β-cell with a GLP-1 receptor agonist.
- 25. The method of claim 24, wherein the GLP-1 receptor agonist is a GLP-1 analog.
- 26. The method of claim 24, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.
- 27. The method of claim 26, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.
- 28. The method of claim 18, wherein the β-cell is a human cell.
- 29. A culture of cells expressing PDX-1, wherein the culture comprises a histone deacetylase inhibitor.
- 30. The culture of claim 29, wherein the cells express a heterologous PDX-1 polynucleotide.
- 31. The culture of claim 29, wherein insulin expression of the cells is at least two-fold higher than cells in a culture lacking the histone deacetylase inhibitor.
- 32. The culture of claim 29, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.
- 33. The culture of claim 29, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline
- 34. The culture of claim 29, wherein the cell expresses a NeuroD polynucleotide.
- 35. The culture of claim 34, wherein the cell expresses a heterologous NeuroD polynucelotide.
- 36. The culture of claim 29, further comprising a GLP-1 receptor agonist.
- 37. The culture of claim 36, wherein the GLP-1 receptor agonist is a GLP-1 analog.
- 38. The culture of claim 36, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.
- 39. The culture of claim 38, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.
- 40. The culture of claim 29, wherein the cells are β-cells.
- 41. The culture of claim 40, wherein the β-cells are human β-cells.
- 42. The culture of claim 29, wherein the β-cells express a recombinant oncogene.
- 43. The culture of claim 42, wherein the β-cells express more than one recombinant oncogene.
- 44. The culture of claim 40, wherein the β-cells express a recombinant telomerase gene.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0001] This invention was made with Government support under Grant No. DK55283, awarded by the National Institutes of Health. The Government has certain rights in this invention.