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.

The endometrium (the inner lining of the uterus) is composed of epithelia and stroma that continually proliferate, differentiate, and shed throughout the menstrual cycle in anticipation of pregnancy (Gellersen and Brosens, 2014; Mihm et al., 2011). The multiple rounds of tissue regression and regeneration that occur throughout a woman’s reproductive years make the endometrium particularly prone to disease (Gargett et al., 2012; Syed et al., 2020; Teixeira et al., 2008). As cyclical tissue breakdown, re-epithelialization, and stromal restoration occurs, the maintenance of proper cell identity is thought to be an important feature of a healthy endometrium (Gellersen and Brosens, 2014). Alterations in normal endometrial function result in numerous conditions, including benign diseases, such as endometrial hyperplasia (Montgomery et al., 2004), adenomyosis (Maheshwari et al., 2012), and endometriosis (Zondervan et al., 2018, 2020), as well as endometrial cancer (Morice et al., 2016) and ovarian cancer (Kurman and Shih, 2016).