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JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin

Lusy Handoko1, Bogumil Kaczkowski1, Chung-Chau Hon1

  • 1a Division of Genomic Technologies , RIKEN Center for Life Science Technologies, Yokohama , Kanagawa , Japan.

Epigenetics
|August 7, 2018
PubMed

Insights

Bromodomain and extra-terminal domain (BET) proteins, like BRD2, associate with histone H4 acetylation at active gene regulatory regions. BET inhibition by JQ1 affects BRD2 binding but not global H4 acetylation, revealing recruitment mechanisms.

Area of Science:

  • Epigenetics and Gene Regulation
  • Cancer Biology
  • Molecular Oncology

Background:

  • Bromodomain and extra-terminal domain (BET) proteins are key epigenetic regulators and drug targets for cancer and immune diseases.
  • While BRD4's role in BET inhibition is well-studied, the function of BRD2 and its genome-wide association with histone H4-hyperacetylated chromatin remain less understood.
  • Understanding BET protein recruitment to chromatin is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the genome-wide association of BRD2 with histone modifications, specifically H4K5acK8ac, at active enhancers and promoters.
  • To elucidate the impact of BET inhibition on BRD2 binding and histone H4 acetylation levels.
  • To identify genes and transcription factors involved in the response to BET inhibition.

Main Methods:

  • Integrated analyses of ChIP-seq and transcriptome profiles at transcription start site (TSS) resolution in the H23 non-small cell lung cancer (NSCLC) cell line.
  • Assessment of BRD2 and histone acetylation marks (H4K5acK8ac, H3K27ac) co-localization.
  • Treatment with the BET inhibitor JQ1 to evaluate changes in BRD2 binding and histone acetylation.

Main Results:

  • BRD2 co-localizes with H4K5acK8ac and H3K27ac at most active enhancers and promoters, with a stronger association observed between BRD2 and H4K5acK8ac.
  • BET inhibition by JQ1 completely abolished BRD2 binding to chromatin but resulted in only localized changes in H4K5acK8ac levels, indicating BRD2 recruitment does not drive global H4 hyperacetylation.
  • A significant number of BRD2-bound genes, including MYC, were transcriptionally upregulated upon JQ1 treatment, suggesting complex regulatory roles and identifying potential transcription factors in JQ1 response.

Conclusions:

  • BRD2 is recruited to chromatin via pre-existing histone H4 hyperacetylation, rather than inducing it, supporting a recruitment model for BET proteins.
  • BET inhibition has distinct effects on BRD2 binding and global histone acetylation.
  • The study identifies BRD2-dependent and -independent mechanisms underlying the transcriptional response to BET inhibition, offering insights for NSCLC therapeutic strategies.
Keywords:
BETBRD2CAGEH4 hyperacetylationJQ1

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