Pharmacological HDAC inhibition impairs pancreatic beta-cell function through an epigenome-wide reprogramming

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 beta cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic beta-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 beta-cell specific transcriptome programming in both mouse and human beta-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative beta-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 beta-cell identity with unsuitable expression of genes associated with alternative cell fates.