Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma

Peter W. Lewis, Manuel M. Müller, Matthew S. Koletsky, Francisco Cordero, Shu Lin, Laura A. Banaszynski, Benjamin A. Garcia, Tom W. Muir, Oren J. Becher, C. David Allis

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594 Scopus citations

Abstract

Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

Original languageEnglish (US)
Pages (from-to)857-861
Number of pages5
JournalScience
Volume340
Issue number6134
DOIs
StatePublished - May 17 2013

ASJC Scopus subject areas

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    Lewis, P. W., Müller, M. M., Koletsky, M. S., Cordero, F., Lin, S., Banaszynski, L. A., Garcia, B. A., Muir, T. W., Becher, O. J., & Allis, C. D. (2013). Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science, 340(6134), 857-861. https://doi.org/10.1126/science.1232245