The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

Abstract

Summary: AT-rich interactive domain-containing proteins 1A and 1B (ARID1A and ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (∼57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that ARID1A binds active regulatory elements in OCCC. Depletion of ARID1A represses RNA polymerase II (RNAPII) transcription but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide insight into ARID1A-mediated tumorigenesis and unveil functions of SWI/SNF in modulating RNAPII dynamics. : Trizzino et al. show that ARID1A regulates RNA polymerase II promoter-proximal pausing in ovarian clear cell carcinoma. Conversely, ARID1A depletion has modest effects on accessibility. Following ARID1A loss, upregulation of ARID1B restores physiological polymerase II dynamics, rescuing transcription. However, multiple p53 and estrogen target genes are strictly dependent on ARID1A. Keywords: SWI/SNF, ovarian clear cell carcinoma, transcription, RNAPII, pausing, ARID1B, ARID1A