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-ß 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. Overall design: Transcriptome profiling of isogenic ARID1A knockout pair of human endometrial epithelial cells