EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains

被引：99

作者：

Donaldson-Collier, Maria C. ^{[1
]}

Sungalee, Stephanie ^{[1
]}

Zufferey, Marie ^{[2
,3
]}

Tavernari, Daniele ^{[2
,3
]}

Katanayeva, Natalya ^{[1
]}

Battistello, Elena ^{[1
,2
,3
]}

Mina, Marco ^{[2
,3
]}

Douglass, Kyle M. ^{[4
]}

Rey, Timo ^{[4
]}

Raynaud, Franck ^{[2
,3
]}

Manley, Suliana ^{[4
]}

Ciriello, Giovanni ^{[2
,3
]}

Oricchio, Elisa ^{[1
]}

机构：

[1] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, Sch Life Sci, Lausanne, Switzerland

[2] Univ Lausanne UNIL, Dept Computat Biol, Lausanne, Switzerland

[3] SIB, Lausanne, Switzerland

[4] Ecole Polytech Fed Lausanne, Inst Phys, Lausanne, Switzerland

来源：

NATURE GENETICS | 2019年 / 51卷 / 03期

基金：

瑞士国家科学基金会; 欧盟地平线“2020”;

关键词：

TOPOLOGICAL DOMAINS; TUMOR-SUPPRESSOR; GENOME; PRINCIPLES; ORGANIZATION; ACTIVATION; LANDSCAPE; LYMPHOMA; DEFINES; TARGET;

D O I：

10.1038/s41588-018-0338-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2. Altered EZH2 (p.Tyr646* (EZH2(Y646X))) led to silencing of entire domains, synergistically inactivating multiple tumor suppressors. Intra-TAD gene silencing was coupled with changes of interactions between gene promoter regions. Notably, gene expression and chromatin interactions were restored by pharmacological inhibition of EZH2(Y646X). Our results indicate that EZH2(Y646X) alters the topology and function of chromatin domains to promote synergistic oncogenic programs.

引用

页码：517 / +

页数：15

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