Bromodomain and extraterminal proteins suppress NF-E2-related factor 2-mediated antioxidant gene expression

J Immunol. 2014 May 15;192(10):4913-4920. doi: 10.4049/jimmunol.1301984. Epub 2014 Apr 14.

Abstract

Oxidative stress, a pathogenetic factor in many conditions, including chronic obstructive pulmonary disease, arises due to accumulation of reactive oxygen species and defective antioxidant defenses in the lungs. The latter is due, at least in part, to impaired activation of NF-E2-related factor 2 (Nrf2), a transcription factor involved in the activation of antioxidant and cytoprotective genes. The bromodomain and extraterminal (BET) proteins, Brd2, Brd3, Brd4, and BrdT, bind to acetylated lysine residues on histone or nonhistone proteins recruiting transcriptional regulators and thus activating or repressing gene transcription. We investigated whether BET proteins modulate the regulation of Nrf2-dependent gene expression in primary human airway smooth muscle cells and the human monocytic cell line, THP-1. Inhibition of BET protein bromodomains using the inhibitor JQ1+ or attenuation of Brd2 and Brd4 expression using small interfering RNA led to activation of Nrf2-dependent transcription and expression of the antioxidant proteins heme oxygenase-1, NADPH quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit. Also, JQ1+ prevented H2O2-induced intracellular reactive oxygen species production. By coimmunoprecipitation, BET proteins were found to be complexed with Nrf2, whereas chromatin-immunoprecipitation studies indicated recruitment of Brd2 and Brd4 to Nrf2-binding sites on the promoters of heme oxygenase-1 and NADPH quinone oxidoreductase 1. BET proteins, particularly Brd2 and Brd4, may play a key role in the regulation of Nrf2-dependent antioxidant gene transcription and are hence an important target for augmenting antioxidant responses in oxidative stress-mediated diseases.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / pharmacology
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Enzymologic / immunology*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / immunology*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Male
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / immunology*
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / immunology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Oxidants / pharmacology
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Oxidative Stress / immunology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology*
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Azepines
  • BRDT protein, mouse
  • Brd2 protein, mouse
  • Brd3 protein, mouse
  • Brd4 protein, mouse
  • Chromosomal Proteins, Non-Histone
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nuclear Proteins
  • Oxidants
  • Transcription Factors
  • Triazoles
  • Hydrogen Peroxide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Protein-Serine-Threonine Kinases