H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

被引：75

作者：

Fang, Dong ^{[1
,2
,6
]}

Gan, Haiyun ^{[1
,2
]}

Cheng, Liang ^{[3
]}

Lee, Jeong-Heon ^{[3
]}

Zhou, Hui ^{[1
,2
]}

Sarkaria, Jann N. ^{[4
]}

Daniels, David J. ^{[5
]}

Zhang, Zhiguo ^{[1
,2
]}

机构：

[1] Columbia Univ, Dept Pediat, Inst Canc Genet, Irving Canc Res Ctr, New York, NY 10027 USA

[2] Columbia Univ, Dept Genet & Dev, Inst Canc Genet, Irving Canc Res Ctr, New York, NY 10027 USA

[3] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA

[4] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA

[5] Mayo Clin, Dept Neurosurg, Rochester, MN USA

[6] Zhejiang Univ, Innovat Ctr Cell Signaling Network, Life Sci Inst, Hangzhou, Zhejiang, Peoples R China

来源：

ELIFE | 2018年 / 7卷

基金：

美国国家卫生研究院;

关键词：

HISTONE H3.3; DNA HYPOMETHYLATION; PEDIATRIC GLIOMA; ACTIVE GENES; CHROMATIN; MUTATIONS; POLYCOMB; INHIBITION; METHYLATION; EXPRESSION;

D O I：

10.7554/eLife.36696

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

引用

页数：23

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