OBJECTIVE: Class IIa 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 IIa 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 IIa HDAC4, -5, and -9 have an unexpected restricted 
expression in the endocrine β- and δ-cells of the pancreas. Analyses of the 
pancreas of class IIa HDAC mutant mice revealed an increased pool of 
insulin-producing β-cells in Hdac5(-/-) and Hdac9(-/-) mice and an increased 
pool of somatostatin-producing δ-cells in Hdac4(-/-) and Hdac5(-/-) mice. 
Conversely, HDAC4 and HDAC5 overexpression showed a decreased pool of 
insulin-producing β-cells and somatostatin-producing δ-cells. Finally, treatment 
of pancreatic explants with the selective class IIa HDAC inhibitor MC1568 
enhances expression of Pax4, a key factor required for proper β-and δ-cell 
differentiation and amplifies endocrine β- and δ-cells.
CONCLUSIONS: We conclude that HDAC4, -5, and -9 are key regulators to control 
the pancreatic β/δ-cell lineage. These results highlight the epigenetic 
mechanisms underlying the regulation of endocrine cell development and suggest 
new strategies for β-cell differentiation-based therapies.