The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
Cell Rep. 2018 Jun 26;23(13):3933-3945. doi: 10.1016/j.celrep.2018.05.097.
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.
富含 AT 的相互作用结构域蛋白 1A 和 1B（ARID1A 和 ARID1B）是染色质重塑 SWI/SNF 的相互排斥的亚基。ARID1A 是所有癌症中最常发生突变的染色质调节剂，而卵巢透明细胞癌（OCCC）具有最高的 ARID1A 突变率（约 57%）。尽管有证据表明 ARID1A 参与了肿瘤发生，但具体机制仍不清楚。在这里，我们证明了 ARID1A 结合了 OCCC 中的活性调节元件。ARID1A 的缺失抑制了 RNA 聚合酶 II（RNAPII）转录，但对可及性的改变不大。具体来说，ARID1A 缺失后，RNAPII 的暂停严重受损。暂停受损导致活性基因的转录失调，这可以通过 ARID1B 的上调来补偿。然而，ARID1A 依赖性基因的一部分不能被 ARID1B 挽救，包括许多 p53 和雌激素受体（ESR1）的靶基因。我们的结果提供了对 ARID1A 介导的肿瘤发生的深入了解，并揭示了 SWI/SNF 在调节 RNAPII 动力学方面的功能。
