BET proteins are required for transcriptional activation of the senescent beta cell secretome in Type 1 Diabetes

OBJECTIVEType 1 Diabetes (T1D) results from progressive loss of pancreatic beta cells due to autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. The objective of this study was to identify transcriptional mechanisms of SASP activation in beta cells.\n\nMETHODSWe used the female NOD mouse model of spontaneous autoimmune T1D and ex vivo experiments on NOD mouse and human islets to test the hypothesis that Bromodomain Extra-Terminal domain (BET) proteins activate the beta cell SASP transcriptional program.\n\nRESULTSHere we show that beta cell SASP is transcriptionally controlled by BET proteins, including BRD4. Chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in beta cells in vivo.\n\nCONCLUSIONSTaken together, our findings support a crucial role for BET proteins in the activation of the beta cell SASP transcriptional program. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.