EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains
EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains
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DOI：
10.1038/s41588-018-0338-y
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发表时间：
2019-03-01
期刊：
影响因子：
30.8
通讯作者：
Oricchio, Elisa
中科院分区：
文献类型：
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作者：
Donaldson-Collier, Maria C.;Sungalee, Stephanie;Oricchio, Elisa
染色质被组织成富含不同组蛋白标记的拓扑关联结构域（TADs）。在癌症中，编码zeste增强子同源物2蛋白（EZH 2）的基因中的功能获得性突变导致与转录抑制相关的组蛋白-3 Lys 27三甲基化（H3 K27 me 3）的全基因组增加。然而，这些表观遗传变化对染色质结构域的结构和功能的影响尚未被探索。在这里，我们发现了TADs与突变EZH 2介导的表观遗传和转录变化之间的功能相互作用。改变的EZH 2（p.Tyr646*（EZH 2（Y 646 X）导致整个结构域的沉默，协同灭活多种肿瘤抑制因子。基因启动子区之间相互作用的改变与基因内沉默相结合。值得注意的是，通过药理学抑制EZH 2（Y 646 X）恢复了基因表达和染色质相互作用。我们的研究结果表明，EZH 2（Y 646 X）改变染色质结构域的拓扑结构和功能，以促进协同致癌程序。
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.