The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets

摘要: To better understand how β-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post-translational modification enriched at active and poised cis-regulatory regions, in IFNγ, Il-1β, TNFα treated pancreatic islets. We identified 96,721 putative loci, which 3,590 were generated de novo, 3,204 had increased H3K4me1, 5,354 decreased H3K4me1 exposed Roughly 10% novo regions for repressive 27 trimethylation (H3K27me3) untreated cells, these frequently associated with chemokine genes. show that exposure overcomes this repression induces gene activation as little three hours, expression persists days absence continued exposure. implicate trithorax group (TrxG) complexes likely players conversion repressed loci an state. block activity complexes, suppressed Wdr5, core component TrxG used H3K27me3 demethylase inhibitor GSK-J4. GSK-J4 is particularly effective blunting TNFα-induced β-cells; however, it induced significant islet-cell apoptosis β-cell dysfunction. Wdr5 suppression also reduced without affecting survival or function after 48hrs, but did begin increase dysfunction four treatment. Taken together data suggest complex potentially viable target preventing cytokine β-cells.