Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages

Cell Death Dis. 2021 Jul 27;12(8):743. doi: 10.1038/s41419-021-04032-9.

Abstract

Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / metabolism
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferons / biosynthesis*
  • Interferons / genetics
  • Lysine / metabolism
  • Macrophages / metabolism*
  • Methylation
  • Mice
  • Promoter Regions, Genetic
  • Protein Binding
  • RAW 264.7 Cells
  • Transcription Factors / metabolism*
  • Vesiculovirus / physiology

Substances

  • Antiviral Agents
  • Arid1a protein, mouse
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Transcription Factors
  • Interferons
  • Histone-Lysine N-Methyltransferase
  • WHSC1 protein, mouse
  • Lysine