title: Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.
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.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.forename: Manuel M
authors.initials: MM
authors.lastname: Müller
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Koletsky
authors.forename: Francisco
authors.initials: F
authors.lastname: Cordero
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.forename: Laura A
authors.initials: LA
authors.lastname: Banaszynski
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Tom W
authors.initials: TW
authors.lastname: Muir
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics*; D002648:Child; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics*; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics; D008715:Methionine / Q000235:genetics; D008745:Methylation; D051379:Mice; D020125:Mutation, Missense; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019076:Transgenes
chemical_list: D006657:Histones; D008715:Methionine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
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