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

Charalambos Michaeloudes1, Nicolas Mercado1, Colin Clarke1

  • 1Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.

Journal of Immunology (Baltimore, Md. : 1950)
|April 16, 2014
PubMed

Insights

Bromodomain and extraterminal (BET) proteins regulate antioxidant gene expression. Inhibiting BET proteins activates Nrf2, enhancing antioxidant defenses and reducing oxidative stress, offering a therapeutic target for related diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Oxidative stress contributes to diseases like COPD due to reactive oxygen species (ROS) and impaired antioxidant defenses.
  • NF-E2-related factor 2 (Nrf2) is crucial for activating antioxidant genes, but its activation can be defective.
  • Bromodomain and extraterminal (BET) proteins (Brd2, Brd3, Brd4, BrdT) regulate gene transcription by binding acetylated proteins.

Purpose of the Study:

  • To investigate if BET proteins modulate Nrf2-dependent gene expression in human airway smooth muscle cells and THP-1 cells.
  • To determine the role of BET proteins in regulating antioxidant gene transcription.
  • To explore BET proteins as potential therapeutic targets for oxidative stress-mediated diseases.

Main Methods:

  • Inhibition of BET protein bromodomains using JQ1+.
  • Attenuation of Brd2 and Brd4 expression using small interfering RNA (siRNA).
  • Coimmunoprecipitation and chromatin-immunoprecipitation assays to study protein interactions and promoter recruitment.

Main Results:

  • Inhibition of BET proteins or Brd2/Brd4 knockdown activated Nrf2-dependent transcription.
  • Expression of antioxidant proteins (heme oxygenase-1, NADPH quinone oxidoreductase 1, glutamate-cysteine ligase catalytic subunit) increased.
  • JQ1+ treatment reduced hydrogen peroxide-induced intracellular ROS production.
  • BET proteins were found complexed with Nrf2 and recruited to antioxidant gene promoters.

Conclusions:

  • BET proteins, particularly Brd2 and Brd4, play a significant role in regulating Nrf2-dependent antioxidant gene transcription.
  • Targeting BET proteins can enhance antioxidant responses.
  • BET proteins represent a promising therapeutic target for augmenting antioxidant defenses in oxidative stress-related conditions.

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