ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

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. [Display omitted] •In endometrial epithelia, ARID1A binding is highly associated with super-enhancers•ARID1A loss leads to super-enhancer H3K27 hyperacetylation and accessibility•P300 inhibition in ARID1A mutant cells suppresses invasion and induces anoikis•SERPINE1 (PAI-1) super-enhancer hyperacetylation drives endometrial invasion 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.