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BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation

Li Zhao1, Yiqi Wang1, Anbalagan Jaganathan2

  • 1Institute of Epigenetic Medicine, First Hospital of Jilin University, Changchun, China.

The EMBO Journal
|January 31, 2023
PubMed

Insights

Bromodomain-containing protein 4 (BRD4) collaborates with Polycomb repressive complex 2 (PRC2) to repress specific genes, enabling T-helper 2 (Th2) cell differentiation. Inhibiting BRD4’s bromodomain 2 blocks this process.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Bromodomain-containing protein 4 (BRD4) is known as a transcriptional activator.
  • Its role in cell type-specific transcriptional repression, particularly in T-helper 2 (Th2) cell differentiation, remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which BRD4 regulates gene repression during Th2 cell lineage differentiation.
  • To investigate the interaction between BRD4 and Polycomb repressive complex 2 (PRC2) in this process.

Main Methods:

  • Utilized mouse primary naïve CD4+ T cells for in vitro differentiation studies.
  • Investigated the binding of BRD4 to the PRC2 complex, specifically the EED subunit.
  • Assessed the impact of BRD4 bromodomain 2 (BD2) inhibition on gene expression and Th2 cell differentiation.

Main Results:

  • BRD4 interacts with PRC2 via its BD2 domain to facilitate histone H3 lysine 27 trimethylation (H3K27me3) and repress Foxp3 and Fbxw7 expression.
  • Repression of Foxp3 and Fbxw7 by BRD4/PRC2 promotes the activation of Th2 cytokines (Il4, Il5, Il13).
  • Chemical inhibition of BRD4 BD2 reversed the repression, downregulating Th2 cytokines and inhibiting Th2 cell differentiation.

Conclusions:

  • BRD4 plays a critical role in orchestrating Th2-specific transcriptional programs by coordinating gene repression and activation.
  • The BRD4-PRC2 interaction is essential for the repression of Th2-negative regulators and subsequent Th2 cell lineage commitment.
  • BRD4's function extends beyond activation to include crucial roles in transcriptional repression, safeguarding cell lineage differentiation.
Keywords:
BRD4PRC2Th2gene repressiongene transcriptional regulation

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