Pharmacological HDAC inhibition impairs pancreatic β-cell function through an epigenome-wide reprogramming
Résumé
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 b cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic b-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 b-cell specific transcriptome programming in both mouse and human b-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative b-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 b-cell identity with unsuitable expression of genes associated with alternative cell fates.
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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