@article{e540b76eb06b41cb91c258327f22fee4,
title = "Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma",
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 = "Automethylation, H3K27M, PRC2, Pediatric glioma, Polycomb",
author = "Lee, {Chul Hwan} and Yu, {Jia Ray} and Jeffrey Granat and Ricardo Salda{\~n}a-Meyer and Joshua Andrade and Gary LeRoy and Ying Jin and Peder Lund and Stafford, {James M.} and Garcia, {Benjamin A.} and Beatrix Ueberheide and Danny Reinberg",
note = "Funding Information: We thank Dr. L. Vales for critical reading of the manuscript as well as past and current Reinberg laboratory members for critical comments and discussion, and L. Popoca, D. Hernandez, and H. Yang and for technical assistance. We also thank Dr. T. Cech for sharing and discussing unpublished data related to this study. We thank H. Zheng from the Biological Mass Spectrometry Facility at Robert Wood Johnson Medical School and Rutgers University for some mass spectrometry analyses. The New York University Flow Cytometry Core, Proteomics Laboratory, and Genome Technology Center were partially supported by the New York University School of Medicine and the Laura and Isaac Perlmutter Cancer Center support grant, National Cancer Institute (P30CA016087). The work in D.R.{\textquoteright}s laboratory is supported by National Institutes of Health (NIH) grant R01CA199652, the Howard Hughes Medical Institute (HHMI), and the Making Headway Foundation St. Baldrick{\textquoteright}s Research Grant (189290). J-R.Y. is supported by the American Cancer Society (PF-17-035-01). J.G. is supported by the Vilcek Scholarship. G.L. is supported by the Making Headway Foundation St. Baldrick{\textquoteright}s Research Grant (189290). J.M.S. was supported as a Simons Foundation Junior Fellow and by NIH grant K99AA024837. The work in B.A.G.{\textquoteright}s laboratory is supported by NIH grants R01GM110174 and P01CA196539. Publisher Copyright: {\textcopyright} 2019 Lee et al.",
year = "2019",
month = oct,
day = "1",
doi = "10.1101/gad.328773.119",
language = "English",
volume = "33",
pages = "1428--1440",
journal = "Genes and Development",
issn = "0890-9369",
number = "19-20",
}