Inactivation of ARID1A-SWI/SNF Complex Alters Chromatin Compactness at Enhancer Regions and Affects Transcription of Key Tumor Signaling Circuitry [RNA-Seq]

Somatic mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human malignancies linked to endometriosis. Through comprehensive chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing, we identified chromatin binding regions for ARID1A/BRG1-containing SWI/SNF remodeling complexes, which were enriched at enhancers and corresponded to a euchromatin state. ARID1A deletion caused global affinity reduction of BRG1-containing complexes in chromatin. Integrative analyses with transcriptome data obtained from endometrial epithelium and human endometrioid carcinomas identified high-confidence ARID1A-regulated genes that participate in tissue regeneration and tumorigenesis. Deletion of Arid1a was found to inactivate the TGF-β pathway and to accelerate tumor progression from pre-cancerous lesions to endometrioid carcinomas. Collectively, this study establishes functional roles of ARID1A mutation and loss in tumor progression. Transcriptome profiling of isogenic ARID1A knockout pair of human endometrial epithelial cells