Format

Send to

Choose Destination
Genes Dev. 2019 Oct 1;33(19-20):1428-1440. doi: 10.1101/gad.328773.119. Epub 2019 Sep 5.

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

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
2
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
3
Proteomics Laboratory, New York University School of Medicine, New York, New York 10016, USA.
4
Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
5
Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
#
Contributed equally

Abstract

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.

KEYWORDS:

H3K27M; PRC2; Polycomb; automethylation; pediatric glioma

PMID:
31488577
PMCID:
PMC6771381
[Available on 2020-04-01]
DOI:
10.1101/gad.328773.119
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center