Vitamin D Switches BAF Complexes to Protect β Cells

• Published in: Cell Vol. 173; no. 5; pp. 1135 - 1149.e15
• Main Authors: Wei, Zong, Yoshihara, Eiji, He, Nanhai, Hah, Nasun, Fan, Weiwei, Pinto, Antonio F.M., Huddy, Timothy, Wang, Yuhao, Ross, Brittany, Estepa, Gabriela, Dai, Yang, Ding, Ning, Sherman, Mara H., Fang, Sungsoon, Zhao, Xuan, Liddle, Christopher, Atkins, Annette R., Yu, Ruth T., Downes, Michael, Evans, Ronald M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-05-2018
• Subjects: Animals; BAF complex; BRD9; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Chromatin Assembly and Disassembly; chromatin remodeling; Chromosomal Proteins, Non-Histone - metabolism; CRISPR screening; diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Humans; inflammation; Insulin - blood; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mutagenesis, Site-Directed; nuclear receptor; Oxidative Phosphorylation - drug effects; PBAF complex; Protein Binding; Receptors, Calcitriol - antagonists & inhibitors; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; RNA Interference; RNA, Guide, CRISPR-Cas Systems - genetics; RNA, Small Interfering - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; VDR; Vitamin D - pharmacology; β cell; VDR; PBAF complex; inflammation; CRISPR screening; chromatin remodeling; BAF complex; β cell; nuclear receptor; BRD9; diabetes
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.04.013

A primary cause of disease progression in type 2 diabetes (T2D) is β cell dysfunction due to inflammatory stress and insulin resistance. However, preventing β cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and β cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore β cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning β cell survival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D.
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•BRD9 and BRD7 bromodomains recognize VDR K91Ac•VDR ligand switches association from BRD9/BAF (inactive) to BRD7/PBAF (active)•Inhibiting BRD9 enhances vitamin D response•Enhanced VDR signaling reduces β cell failure and curbs T2D progression
Modulation of a ligand-dependent switch between VDR-associated chromatin remodeling complexes enhances vitamin D response in β cells and curbs T2D progression.