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A natural product targets BRD4 to inhibit phase separation and gene transcription

Cong Wang1,2, Huasong Lu2,3, Xiangzhong Liu1

  • 1State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.

Iscience
|January 24, 2022
PubMed

Insights

A natural compound, PCG, from Polygonum cuspidatum, inhibits the bromodomain and extra-terminal (BET) protein BRD4. It disrupts BRD4

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Pharmacology

Background:

  • The BET protein BRD4 plays a crucial role in gene transcription by binding to acetyl-histones and recruiting transcription factors.
  • BRD4's function is linked to its ability to form phase-separated condensates at super-enhancer regions of genes.
  • Dysregulation of BRD4 is implicated in diseases like cancer.

Purpose of the Study:

  • To identify novel inhibitors of BRD4.
  • To investigate the mechanism of action of a natural product targeting BRD4.
  • To explore the role of phase separation in BRD4-mediated transcription inhibition.

Main Methods:

  • Identification and isolation of natural product PCG from Polygonum cuspidatum.
  • Biochemical assays to confirm direct binding of PCG to BRD4.
  • Analysis of BRD4 phase separation and condensate formation in the presence of PCG.
  • Assessment of transcriptional activity of BRD4-dependent genes upon PCG treatment.

Main Results:

  • PCG was identified as a natural product that directly binds to BRD4.
  • PCG inhibits BRD4's ability to form phase-separated condensates.
  • PCG treatment converts dynamic BRD4 condensates into static aggregates.
  • This inhibition effectively shuts down the transcription of BRD4-dependent genes, including proto-oncogenes and cell identity genes.

Conclusions:

  • PCG is a novel BET inhibitor that selectively targets BRD4.
  • PCG's mechanism of action involves suppressing BRD4 phase separation, a novel approach compared to existing BET inhibitors.
  • PCG represents a promising therapeutic lead for diseases driven by BRD4.
Keywords:
Biological sciencesMolecular biologyNatural product biochemistry

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