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

  1. Raphaël Scharfmann1
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM) U845, Research Center Growth and Signalling, Paris Descartes University, Sorbonne Paris Cité, Necker Hospital, Paris, France
  2. 2INSERM Unité Mixte de Recherche (UMR)-S 872, Cordeliers Research Center, Paris, France
  3. 3Pasteur Institute-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
  4. 4Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
  5. 5Institute of Brain and Spinal Cord Research Center, Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM UMR-S 975, Pierre and Marie Curie University, Pitié Salpêtrière Hospital, Paris, France
  1. Corresponding author: Cécile Haumaitre, cecile.haumaitre{at}inserm.fr, or Raphaël Scharfmann, raphael.scharfmann{at}inserm.fr.
  1. C.H. and R.S. contributed equally to this study.

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.

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.

Footnotes

  • Received April 4, 2011.
  • Accepted August 16, 2011.

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  1. Diabetes vol. 60 no. 11 2861-2871
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