Vitamin D Switches BAF Complexes to Protect β Cells
Copyright policy )Vitamin D Switches BAF Complexes to Protect β Cells
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.
- University of Sydney Australia
- Howard Hughes Medical Institute United States
- Salk Institute for Biological Studies United States
- Westmead Hospital Australia
Male, Chromosomal Proteins, Non-Histone, Mice, Obese, RNA, Guide, CRISPR-Cas Systems, Chromatin Assembly and Disassembly, Oxidative Phosphorylation, Diabetes Mellitus, Experimental, Mice, Inbred C57BL, Mice, Calcitriol, Insulin-Secreting Cells, Mutagenesis, Site-Directed, Animals, Humans, Insulin, Receptors, Calcitriol, RNA Interference, RNA, Small Interfering, Protein Binding, Transcription Factors
Male, Chromosomal Proteins, Non-Histone, Mice, Obese, RNA, Guide, CRISPR-Cas Systems, Chromatin Assembly and Disassembly, Oxidative Phosphorylation, Diabetes Mellitus, Experimental, Mice, Inbred C57BL, Mice, Calcitriol, Insulin-Secreting Cells, Mutagenesis, Site-Directed, Animals, Humans, Insulin, Receptors, Calcitriol, RNA Interference, RNA, Small Interfering, Protein Binding, Transcription Factors
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