ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation.
ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation.
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ARID1A突变通过超级增强子高乙酰化促进P300依赖的子宫内膜侵袭。
DOI：
10.1016/j.celrep.2020.108366
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发表时间：
2020-11-10
期刊：
影响因子：
8.8
通讯作者：
Chandler RL
中科院分区：
文献类型：
--
作者：
Wilson MR;Reske JJ;Holladay J;Neupane S;Ngo J;Cuthrell N;Wegener M;Rhodes M;Adams M;Sheridan R;Hostetter G;Alotaibi FT;Yong PJ;Anglesio MS;Lessey BA;Leach RE;Teixeira JM;Missmer SA;Fazleabas AT;Chandler RL
子宫内膜异位症影响十分之一的妇女，其特点是在异位部位存在异常子宫内膜。ARID1A突变在深度侵袭性疾病中观察到，通常与恶性肿瘤相关。为了确定驱动入侵的表观遗传依赖性，我们使用无偏倚的方法来绘制子宫内膜中伴随ARID1A丢失的染色质状态转变。我们发现高H3K27乙酰化标记的超级增强子与ARID1A结合密切相关。ARID1A缺失导致H3K27超乙酰化，并增加超增强子的染色质可及性和增强子RNA转录，但不影响典型增强子，这表明ARID1A通常阻止超增强子的超激活。ARID1A在超增强子上与P300共定位，在ARID1A突变的子宫内膜上皮中，基因或药物抑制P300可通过超增强子超乙酰化的拯救来抑制入侵并诱导anoikis。在超激活的超级增强子中，SERPINE1 （PAI-1）被认为是驱动ARID1A突变型子宫内膜侵袭的重要靶基因。总的来说，我们的研究结果为针对ARID1A突变子宫内膜的超增强子的治疗策略提供了基本原理。在深度侵袭性子宫内膜异位症中观察到ARID1A突变。在这里，Wilson等人表明ARID1A可以阻止超增强子的H3K27超乙酰化。在arid1a突变子宫内膜中抑制P300可挽救超增强子超乙酰化并抑制侵袭。SERPINE1 （PAI-1）超增强子超乙酰化驱动arid1a突变体子宫内膜的侵袭。侵袭性子宫内膜异位症可能对超增强剂靶向治疗敏感。
Endometriosis affects 1 in 10 women and is characterized by the presence of abnormal endometrium at ectopic sites. ARID1A mutations are observed in deeply invasive forms of the disease, often correlating with malignancy. To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium. We show that super-enhancers marked by high H3K27 acetylation are strongly associated with ARID1A binding. ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation. ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1A mutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1A mutant endometrial invasion. Broadly, our findings provide rationale for therapeutic strategies targeting super-enhancers in ARID1A mutant endometrium. ARID1A mutations are observed in deeply invasive endometriosis. Here, Wilson et al. show that ARID1A prevents H3K27 hyperacetylation of super-enhancers. Inhibition of P300 in ARID1A-mutant endometrium rescues super-enhancer hyperacetylation and inhibits invasion. SERPINE1 (PAI-1) super-enhancer hyperacetylation drives the invasion of ARID1A-mutant endometrium. Invasive endometriosis may be sensitive to super-enhancer-targeted therapies.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
4.7
作者：
Bilyk O;Coatham M;Jewer M;Postovit LM
通讯作者：
Postovit LM
DOI：
10.1056/nejmoa1614814
发表时间：
2017-05-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Anglesio MS;Papadopoulos N;Ayhan A;Nazeran TM;Noë M;Horlings HM;Lum A;Jones S;Senz J;Seckin T;Ho J;Wu RC;Lac V;Ogawa H;Tessier-Cloutier B;Alhassan R;Wang A;Wang Y;Cohen JD;Wong F;Hasanovic A;Orr N;Zhang M;Popoli M;McMahon W;Wood LD;Mattox A;Allaire C;Segars J;Williams C;Tomasetti C;Boyd N;Kinzler KW;Gilks CB;Diaz L;Wang TL;Vogelstein B;Yong PJ;Huntsman DG;Shih IM
通讯作者：
Shih IM
影响因子：
11.2
作者：
Adams, Jessica R.;Xu, Keli;Egan, Sean E.
通讯作者：
Egan, Sean E.
影响因子：
7.2
作者：
Bedaiwy, Mohamed A.;Falcone, Tommaso;Casper, Robert F.
通讯作者：
Casper, Robert F.