In type 2 diabetes (T2D), inflammation induces massive changes in beta cell transcriptome and epigenome, resulting in eventual dysfunction and death of beta cells. Accordingly, strategies designed to protect beta cells from inflammatory stress at transcriptional and epigenetic level could be attractive for combating diabetes. Through genome-wide CRISPR screening in human stem cell differentiated islet like organoids, we identified a novel mechanism connecting signal- dependent transcription by vitamin D receptor (VDR) and fine-tuning of chromatin accessibility by a balance between two SWI/SNF complexes, BAF and PBAF. Our studies revealed that VDR recruits BAF and PBAF complexes through two bromodomain proteins, BRD9 and BRD7, respectively. The balance between BAF-BRD9 and PBAF-BRD7 determines the VDR-driven anti-inflammatory and pro-survival response in pancreatic beta cells. In a dual regulatory mechanism, inhibition of the VDR-BRD9 interaction in combination with ligand activation of VDR cooperate to dismiss the BAF-BRD9 complex and shift the balance to the activating PBAF-BRD7 complex to induce a coordinated transcriptional response. Notably, pharmacologically potentiated VDR signaling by a synthetic ligand in combination with a BRD9 inhibitor can partially restore beta cell function and glucose homeostasis in various T2D mouse models. Tissue specific models further confirmed the functional role of VDR and BRD9 in beta cell stress response in vivo. Together, our results revealed that an unexpected epigenetic balance between the bromodomain readers has a major impact on beta cell survival and glucose homeostasis, and demonstrated the therapeutic potential of targeting inflammatory/metabolic stress through synergistic modulation of hormone receptors and chromatin accessibility.
Z. Wei: None.
National Institutes of Health (1K01DK120808)