2117-P: BET Bromodomain Inhibitors Mitigate Cytokine-Induced Transcription in ß-Cells via Inhibition of Nf-κB

Abstract

Type 1 diabetes is an autoimmune disease characterized by chronic inflammation of pancreatic islets, mediated by proinflammatory cytokines, leading to reduced response to glucose and ultimately selective destruction of insulin-producing β-cells. In common with many autoimmune diseases, the exact causes are poorly understood. Although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins suggest an, as yet undetermined, contribution of epigenetic factors. Recent studies have begun to explore the contributions of epigenetic regulatory proteins in onset and progression of autoimmune diabetes. An important class of epigenetic “readers” is the bromodomain and extraterminal domain (BET) family (Brd2, Brd3, Brd4, and Brdt), which has emerged as promising drug targets for a wide variety of diseases. A unique trait of the BET family is that these proteins contain two bromodomains (BD1 and BD2) that afford them the capacity to simultaneously bind two acetylated histones and/or non-histone proteins such as DNA-binding factors to modulate transcription in a cell-type specific manner. Here, we use an insulinoma β-cell line (INS832/13) and primary rat islets to investigate the ability of chemical inhibitors of BET bromodomain proteins to decrease the β-cell response to proinflammatory cytokines. We found that BET inhibitors mitigated cytokine-induced transcription of inflammatory mediators known to damage β-cells. This is mediated through the inhibition of the NF-κB pathway by BET inhibitors. Furthermore, using CRISPR/Cas9 knockout insulinoma β-cell lines of Brd2, Brd3, and Brd4 and BD1 vs. BD2 specific chemical inhibitors, we identified key mechanisms through which this altered transcriptional profile occurs. This work provides important mechanistic insights to disease onset and progression of autoimmune diabetes for which current therapies are ineffective. Disclosure J. Nord: None. S. Wynia-Smith: None. B.C. Smith: None. Funding American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119359)