Abstract PO008: ARID1A prevents H3K27-hyperacetylation at active super-enhancers

Abstract

Abstract Mutations in the multi-subunit SWI/SNF (BAF) chromatin remodeling complex are observed in nearly all types of cancer. The most highly mutated subunit across cancer is ARID1A, which occurs in roughly half of uterine endometrial cancer cases. ARID1A mutations and loss of expression are also common in endometriosis. We have previously demonstrated that ARID1A loss drives transcriptional alterations leading to invasive phenotypes through multiple model systems. Yet, how ARID1A regulates transcription through chromatin regulation is poorly understood. We have generated genome-wide profiles of seven chromatin features associated with transcriptional regulation in human endometrial epithelial cells, in both the presence and absence of ARID1A, in order to identify a mechanism by which ARID1A regulates chromatin. Unbiased genome segmentation using these features revealed that ARID1A interacts with chromatin at highly active and accessible enhancers genome-wide. Out of all tested chromatin features, ARID1A most strongly co-localizes with H3K27ac, a mark of transcriptional activation at proximal and distal enhancers. ARID1A depletion also displayed the greatest effect on genomic H3K27ac as opposed to other histone modifications, H3K18ac, H3K4me1, H3K4me3, and H3K27me3. While the majority of typical enhancers had reduced H3K27ac with ARID1A loss, super-enhancers marked by high basal H3K27ac levels displayed hyperacetylation following ARID1A loss. Moreover, increasing H3K27ac was also associated with heightened eRNA transcription, indicating enhancer hyperactivation. Finally, RNA-seq revealed that genes associated with active super-enhancers were preferentially dysregulated following ARID1A loss. These results suggest that ARID1A-SWI/SNF differentially regulate typical enhancers vs. super-enhancers in the endometrial epithelium, and ARID1A may normally restrict super-enhancer hyperactivation to maintain epithelial identity and prevent endometrial invasion. Citation Format: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler. ARID1A prevents H3K27-hyperacetylation at active super-enhancers [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO008.