Pharmacological HDAC inhibition impairs pancreatic β-cell function through an epigenome-wide reprogramming
Frédérik Oger, Maeva Moreno, Mehdi Derhourhi, Bryan Thiroux, Lionel Berberian, Cyril Bourouh, Emmanuelle Durand, Souhila Amanzougarene, Alaa Badreddine, Étienne Blanc, Olivier Molendi‐Coste, Laurent Pineau, Gianni Pasquetti, Laure Rolland, Charlène Carney, Florine Bornaque, Émilie Courty, Céline Gheeraert, Jérôme Eeckhoute, David Dombrowicz, Julie Kerr‐Conte, François Pattou, Bart Staels, Philippe Froguel, Amélie Bonnefond, Jean‐Sébastien Annicotte
Abstract
Histone deacetylases enzymes (HDACs) are chromatin modifiers that regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic β cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic β-cell identity and function using the pan-HDAC inhibitor trichostatin A through chromatin immunoprecipitation assays and RNA sequencing experiments. We observed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that HDAC activity could be required to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.