Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

被引：987

作者：

Lewis, Peter W. ^{[1
]}

Mueller, Manuel M. ^{[2
]}

Koletsky, Matthew S. ^{[1
]}

Cordero, Francisco ^{[3
,4
]}

Lin, Shu ^{[5
]}

Banaszynski, Laura A. ^{[1
]}

Garcia, Benjamin A. ^{[5
]}

Muir, Tom W. ^{[2
]}

Becher, Oren J. ^{[3
,4
]}

Allis, C. David ^{[1
]}

机构：

[1] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA

[2] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA

[3] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Dept Pediat, Durham, NC 27710 USA

[4] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Dept Pathol, Durham, NC 27710 USA

[5] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

来源：

SCIENCE | 2013年 / 340卷 / 6134期

关键词：

HISTONE MARKS; BINDING;

D O I：

10.1126/science.1232245

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：857 / 861

页数：5

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