Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Cell Rep. 2020 Nov 10;33(6):108366. doi: 10.1016/j.celrep.2020.108366.
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.
子宫内膜异位症影响十分之一的女性，其特征是异位存在异常的子宫内膜。ARID1A 突变可见于疾病的深部浸润形式，常与恶性肿瘤相关。为了确定驱动侵袭的表观遗传依赖性，我们采用一种无偏的方法来绘制伴随子宫内膜 ARID1A 缺失的染色质状态转变图谱。我们表明，由高 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，并增加超级增强子处的染色质可及性和增强子 RNA 转录，但不增加典型增强子，表明 ARID1A 通常可防止超级增强子过度激活。ARID1A 与 P300 在超级增强子上共定位，在 ARID1A 突变的子宫内膜上皮细胞中，通过拯救超级增强子的过度乙酰化，遗传或药理学抑制 P300 可抑制侵袭并诱导细胞凋亡。在过度激活的超级增强子中，SERPINE1（PAI-1）被鉴定为驱动 ARID1A 突变子宫内膜侵袭的必需靶基因。总的来说，我们的研究结果为针对 ARID1A 突变的子宫内膜中的超级增强子的治疗策略提供了依据。
