title: Specific control of pancreatic endocrine β- and δ-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9.
abstract: 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.
  
  
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U845, Research Center Growth and Signalling, Paris Descartes University, Sorbonne Paris Cité, Necker Hospital, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lenoir
authors.forename: Kathleen
authors.initials: K
authors.lastname: Flosseau
authors.forename: Feng Xia
authors.initials: FX
authors.lastname: Ma
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Cécile
authors.initials: C
authors.lastname: Haumaitre
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
mesh_terms: D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size; D009928:Organ Specificity; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D007328:Insulin; D007527:Isoenzymes; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D013004:Somatostatin; C498618:Hdac5 protein, mouse; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases