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BRCA1 is a negative modulator of the PRC2 complex

Lan Wang1, Xianzhuo Zeng, Shuai Chen

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.

The EMBO Journal
|April 30, 2013
PubMed

Insights

The tumor suppressor BRCA1 negatively regulates Polycomb Repressive Complex 2 (PRC2) by interacting with EZH2. Loss of BRCA1 impairs stem cell differentiation and promotes aggressive breast cancer via PRC2.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Biology

Background:

  • Polycomb-repressive complex 2 (PRC2) epigenetically regulates gene expression by catalyzing histone H3 lysine 27 trimethylation (H3K27me3).
  • PRC2 is crucial for maintaining stem cell pluripotency and suppressing differentiation.
  • Aberrant PRC2 activity is implicated in various cancers, including breast cancer.

Purpose of the Study:

  • To investigate the interaction between tumor suppressor BRCA1 and PRC2 component EZH2.
  • To elucidate the role of BRCA1 in modulating PRC2 function in embryonic stem cells and breast cancer.

Main Methods:

  • Co-immunoprecipitation assays to detect BRCA1-EZH2 interaction.
  • RNA immunoprecipitation followed by sequencing (RIP-seq) to assess EZH2 binding to HOTAIR ncRNA.
  • Chromatin immunoprecipitation (ChIP) to quantify H3K27me3 levels.
  • Cell differentiation assays in mouse embryonic stem cells.
  • Cell migration and invasion assays in human breast cancer cells.

Main Results:

  • BRCA1 directly interacts with EZH2, inhibiting its binding to HOTAIR ncRNA.
  • BRCA1 deficiency leads to genome-wide EZH2 re-targeting and increased H3K27me3 levels at PRC2 target loci.
  • Loss of BRCA1 impairs mouse embryonic stem cell differentiation and enhances human breast cancer cell migration and invasion.
  • These effects are dependent on EZH2 activity.

Conclusions:

  • BRCA1 acts as a critical negative regulator of PRC2 activity.
  • Loss of BRCA1 function disrupts stem cell homeostasis and promotes an aggressive breast cancer phenotype through aberrant PRC2 modulation.

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