Vitamin D Switches BAF Complexes to Protect β Cells

Cell. 2018 May 17;173(5):1135-1149.e15. doi: 10.1016/j.cell.2018.04.013. Epub 2018 May 10.

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.

Keywords: BAF complex; BRD9; CRISPR screening; PBAF complex; VDR; chromatin remodeling; diabetes; inflammation; nuclear receptor; β cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitriol / analogs & derivatives
  • Calcitriol / pharmacology
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Humans
  • 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
  • Oxidative Phosphorylation / drug effects
  • Protein Binding
  • RNA Interference
  • RNA, Guide / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Calcitriol / antagonists & inhibitors
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Vitamin D / pharmacology*

Substances

  • Brd9 protein, mouse
  • Chromosomal Proteins, Non-Histone
  • Insulin
  • RNA, Guide
  • RNA, Small Interfering
  • Receptors, Calcitriol
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • Vitamin D
  • calcipotriene
  • Calcitriol