Bromodomain protein Brd3 promotes Ifnb1 transcription via enhancing IRF3/p300 complex formation and recruitment to Ifnb1 promoter in macrophages

Sci Rep. 2017 Jan 3;7:39986. doi: 10.1038/srep39986.

Abstract

As members of bromodomain and extra-terminal motif protein family, bromodomain-containing proteins regulate a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression and transcriptional regulation. The function of these bromodomain proteins (Brds) in innate immune response has been reported but the role of Brd3 remains unclear. Here we find that virus infection significantly downregulate Brd3 expression in macrophages and Brd3 knockout inhibits virus-triggered IFN-β production. Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection. Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. Therefore, our work indicated that Brd3 may act as a coactivator in IRF3/p300 transcriptional activation of Ifnb1 and provided new epigenetic mechanistic insight into the efficient activation of the innate immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • CRISPR-Cas Systems / genetics
  • Cells, Cultured
  • E1A-Associated p300 Protein / metabolism*
  • Histones / metabolism
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / virology
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • RAW 264.7 Cells
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transcription Factors
  • Transcriptional Activation
  • Viruses / pathogenicity

Substances

  • Brd3 protein, mouse
  • Histones
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • Interferon-beta
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse