Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice

JCI Insight. 2020 Jul 23;5(14):e137127. doi: 10.1172/jci.insight.137127.


Tissue regeneration capacity declines with aging in association with heightened oxidative stress. Expression of the oxidant-generating enzyme, NADPH oxidase 4 (Nox4), is elevated in aged mice with diminished capacity for fibrosis resolution. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal (BET) family of proteins that function as epigenetic "readers" of acetylated lysine groups on histones. In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. BET inhibition interferes with the association of Brd4, p300, and acetylated histone H4K16 with the Nox4 promoter in lung fibroblasts stimulated with the profibrotic cytokine, TGF-β1. A number of BET inhibitors, including I-BET-762, JQ1, and OTX015, downregulate Nox4 gene expression and activity. Aged mice with established and persistent lung fibrosis recover capacity for fibrosis resolution with OTX015 treatment. This study implicates epigenetic regulation of Nox4 by Brd4 and p300 and supports BET/Brd4 inhibition as an effective strategy for the treatment of age-related fibrotic lung disease.

Keywords: Aging; Cell Biology; Epigenetics; Fibrosis.

Publication types

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

MeSH terms

  • Acetanilides / pharmacology
  • Aging / genetics
  • Aging / pathology
  • Animals
  • Azepines / pharmacology
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Histones / genetics
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • NADPH Oxidase 4 / genetics*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / pathology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transforming Growth Factor beta1 / genetics
  • Triazoles / pharmacology
  • p300-CBP Transcription Factors / genetics*


  • (+)-JQ1 compound
  • Acetanilides
  • Azepines
  • Brd4 protein, mouse
  • Heterocyclic Compounds, 3-Ring
  • Histones
  • Nuclear Proteins
  • OTX015
  • Tgfb1 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Triazoles
  • NADPH Oxidase 4
  • Nox4 protein, mouse
  • p300-CBP Transcription Factors