Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.
Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.
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DOI：
10.1126/science.1232245
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发表时间：
2013-05-17
期刊：
影响因子：
--
通讯作者：
Allis CD
中科院分区：
文献类型：
--
作者：
Lewis PW;Müller MM;Koletsky MS;Cordero F;Lin S;Banaszynski LA;Garcia BA;Muir TW;Becher OJ;Allis CD
儿童神经胶质瘤的测序已经在编码组蛋白H3.3（H3 F3 A）和H3.1（HIST 3 H1B）的基因中鉴定出错义突变Lys 27 Met（K27 M）和Gly 34 Arg/瓦尔（G34 R/V）。我们报告说，人弥漫性内在脑桥胶质瘤（DIPG）含有K27 M突变显示显着较低的H3与三甲基赖氨酸27（H3 K27 me 3）的总量和组蛋白H3 K27 M转基因足以减少H3 K27 me 3在体外和体内的量。我们发现H3 K27 M通过与EZH 2亚基相互作用抑制Polycomb阻遏复合物2的酶活性。此外，在其他已知的甲基化赖氨酸（H3 K9和H3 K36）处含有赖氨酸至甲硫氨酸取代的转基因足以通过抑制SET结构域酶而引起甲基化的特异性降低。我们建议，K到M的取代可能代表了一种机制，以改变表观遗传状态在各种病理。
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.
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在遗传学和组织学精确的脑干神经胶质瘤模型中，辐射和perifosine的临床前评估。
影响因子：
11.2
作者：
Becher OJ;Hambardzumyan D;Walker TR;Helmy K;Nazarian J;Albrecht S;Hiner RL;Gall S;Huse JT;Jabado N;MacDonald TJ;Holland EC
通讯作者：
Holland EC
影响因子：
30.8
作者：
Wu, Gang;Broniscer, Alberto;McEachron, Troy A.;Lu, Charles;Paugh, Barbara S.;Becksfort, Jared;Qu, Chunxu;Ding, Li;Huether, Robert;Parker, Matthew;Zhang, Junyuan;Gajjar, Amar;Dyer, Michael A.;Mullighan, Charles G.;Gilbertson, Richard J.;Mardis, Elaine R.;Wilson, Richard K.;Downing, James R.;Ellison, David W.;Zhang, Jinghui;Baker, Suzanne J.
通讯作者：
Baker, Suzanne J.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Margueron, Raphael;Reinberg, Danny
通讯作者：
Reinberg, Danny
DOI：
10.1073/pnas.1012525107
发表时间：
2010-12-07
影响因子：
11.1
作者：
Sneeringer, Christopher J.;Scott, Margaret Porter;Copeland, Robert A.
通讯作者：
Copeland, Robert A.