rat INS-1 cells, mouse pancreatic islets Transcriptome

The primary cause of disease progression in type 2 diabetes (T2D) is inflammatory stress-induced ß cell dysfunction, however preservation of ß cell function under diabetic conditions remains challenging. Here we identify the vitamin D receptor (VDR) as a key modulator of the inflammatory response in ß cells. Notably, we uncover a ligand-dependent switch between the BAF and PBAF chromatin remodeling complexes mediated by the alternate binding of bromodomain-containing protein (BRD) 9 and BRD7, respectively to acetylated VDR. Mechanistically, BRD9 inhibition synergistically cooperates with ligand-dependent VDR activation to abrogate cytokine-induced transcriptomic changes, in part via PBAF-mediated changes in chromatin accessibility and enhancer landscape. Importantly, combined VDR activation and BRD9 inhibition significantly restored ß cell function to ameliorate hyperglycemia in multiple murine T2D models. Our studies establish the VDR-BRD9 as a central hub in orchestrating ß cell anti-inflammatory responses and demonstrate its therapeutic potential in T2D.