Vitamin D Switches BAF Complexes to Protect β Cells

Zong Wei, Eiji Yoshihara, Nanhai He, Nasun Hah, Weiwei Fan, Antonio F.M. Pinto, Timothy Huddy, Yuhao Wang, Brittany Ross, Gabriela Estepa, Yang Dai, Ning Ding, Mara H. Sherman, Sungsoon Fang, Xuan Zhao, Christopher Liddle, Annette R. Atkins, Ruth T. Yu, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1135-1149.e15
JournalCell
Volume173
Issue number5
DOIs
StatePublished - May 17 2018

Keywords

  • BAF complex
  • BRD9
  • CRISPR screening
  • PBAF complex
  • VDR
  • chromatin remodeling
  • diabetes
  • inflammation
  • nuclear receptor
  • β cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Wei, Z., Yoshihara, E., He, N., Hah, N., Fan, W., Pinto, A. F. M., Huddy, T., Wang, Y., Ross, B., Estepa, G., Dai, Y., Ding, N., Sherman, M. H., Fang, S., Zhao, X., Liddle, C., Atkins, A. R., Yu, R. T., Downes, M., & Evans, R. M. (2018). Vitamin D Switches BAF Complexes to Protect β Cells. Cell, 173(5), 1135-1149.e15. https://doi.org/10.1016/j.cell.2018.04.013