Specific Control of Pancreatic Endocrine β- and δ-Cell Mass by Class IIa Histone Deacetylases HDAC4, HDAC5, and HDAC9

OBJECTIVE-Class Ha histone deacetylases (HDACs) belong to a large family of enzymes involved in protein deacetylation and play a role in regulating gene expression and cell differentiation. Previously, we showed that HDAC inhibitors modify the timing and determination of pancreatic cell fate. The aim of this study was to determine the role of class Ha HDACs in pancreas development. RESEARCH DESIGN AND METHODS-We took a genetic approach and analyzed the pancreatic phenotype of mice lacking HDAC4, -5, and -9. We also developed a novel method of lentiviral infection of pancreatic explants and performed gain-of-function experiments. RESULTS-We show that class Ha HDAC4, -5, and -9 have an unexpected restricted expression in the endocrine beta- and delta-cells of the pancreas. Analyses of the pancreas of class IIa HDAC mutant mice revealed an increased pool of insulin-producing beta-cells in Hdac5(-/-) and Hdac9(-/-) mice and an increased pool of somatostatin-producing delta-cells in Hdac4(-/-) and Hdac5(-/-) mice. Conversely, HDAC4 and HDAC5 overexpression showed a decreased pool of insulin-producing beta-cells and somatostatin-producing delta-cells. Finally, treatment of pancreatic explants with the selective class IIa HDAC inhibitor MC1568 enhances expression of Pax4, a key factor required for proper beta-and delta-cell differentiation and amplifies endocrine beta- and delta-cells. CONCLUSIONS-We conclude that HDAC4, -5, and -9 are key regulators to control the pancreatic beta/delta-cell lineage. These results highlight the epigenetic mechanisms underlying the regulation of endocrine cell development and suggest new strategies for beta-cell differentiation-based therapies. Diabetes 60:2861-2871, 2011