BRCA1 is a negative modulator of the PRC2 complex

Lan Wang, Xianzhuo Zeng, Shuai Chen, Liya Ding, Jian Zhong, Jonathan C. Zhao, Liguo Wang, Aaron Sarver, Antonius Koller, Jizu Zhi, Yupo Ma, Jindan Yu, Junjie Chen, Haojie Huang*

*Corresponding author for this work

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

The Polycomb-repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation genes. Here we show that the tumour-suppressor protein BRCA1 interacts with the Polycomb protein EZH2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the noncoding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes genome-wide EZH2 re-targeting and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances an aggressive breast cancer phenotype by affecting PRC2 function.

Original languageEnglish (US)
Pages (from-to)1584-1597
Number of pages14
JournalEMBO Journal
Volume32
Issue number11
DOIs
StatePublished - May 29 2013

Keywords

  • BRCA1
  • PRC2
  • breast cancer
  • embryonic stem cell
  • epigenetic gene silencing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Wang, L., Zeng, X., Chen, S., Ding, L., Zhong, J., Zhao, J. C., Wang, L., Sarver, A., Koller, A., Zhi, J., Ma, Y., Yu, J., Chen, J., & Huang, H. (2013). BRCA1 is a negative modulator of the PRC2 complex. EMBO Journal, 32(11), 1584-1597. https://doi.org/10.1038/emboj.2013.95