@article{66b69ea108714daaac8c8651032c0867,
title = "Vitamin D Switches BAF Complexes to Protect β Cells",
abstract = "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. Modulation of a ligand-dependent switch between VDR-associated chromatin remodeling complexes enhances vitamin D response in β cells and curbs T2D progression.",
keywords = "BAF complex, BRD9, CRISPR screening, PBAF complex, VDR, chromatin remodeling, diabetes, inflammation, nuclear receptor, β cell",
author = "Zong Wei and Eiji Yoshihara and Nanhai He and Nasun Hah and Weiwei Fan and Pinto, {Antonio F.M.} and Timothy Huddy and Yuhao Wang and Brittany Ross and Gabriela Estepa and Yang Dai and Ning Ding and Sherman, {Mara H.} and Sungsoon Fang and Xuan Zhao and Christopher Liddle and Atkins, {Annette R.} and Yu, {Ruth T.} and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: We thank D. Hargreaves and C. Benner for discussion, L. Chuong, H. Juguilon, and B. Collins for technical support, E. Ong and C. Brondos for administrative support, and all Evans lab members for discussion. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology, and is supported by NIH ( DK057978 , HL088093 , HL105278 , and ES010337 ), NIEHS ( P42ES010337 ), the Glenn Foundation for Medical Research , the Leona M. and Harry B. Helmsley Charitable Trust ( 2017PG-MED001 ), Ipsen/Biomeasure , California Institute for Regenerative Medicine ( RB5-07394 ), The Ellison Medical Foundation , and by a gift from Steven and Lisa Altman . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported by Salk Cores (see STAR Methods ). Funding Information: We thank D. Hargreaves and C. Benner for discussion, L. Chuong, H. Juguilon, and B. Collins for technical support, E. Ong and C. Brondos for administrative support, and all Evans lab members for discussion. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology, and is supported by NIH (DK057978, HL088093, HL105278, and ES010337), NIEHS (P42ES010337), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust (2017PG-MED001), Ipsen/Biomeasure, California Institute for Regenerative Medicine (RB5-07394), The Ellison Medical Foundation, and by a gift from Steven and Lisa Altman. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was supported by Salk Cores (see STAR Methods). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "17",
doi = "10.1016/j.cell.2018.04.013",
language = "English (US)",
volume = "173",
pages = "1135--1149.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}