4.7 Article

Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma

期刊

GENES & DEVELOPMENT
卷 33, 期 19-20, 页码 1428-1440

出版社

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.328773.119

关键词

automethylation; H3K27M; PRC2; pediatric glioma; Polycomb

资金

  1. New York University School of Medicine
  2. Laura and Isaac Perlmutter Cancer Center support grant, National Cancer Institute [P30CA016087]
  3. National Institutes of Health (NIH) [R01CA199652]
  4. Howard Hughes Medical Institute (HHMI)
  5. Making Headway Foundation St. Baldrick's Research Grant [189290]
  6. American Cancer Society [PF-17-035-01]
  7. Vilcek Scholarship
  8. NIH [K99AA024837, R01GM110174, P01CA196539]
  9. NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER

向作者/读者索取更多资源

The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.

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