The tumor suppressor ARID1A controls global transcription via pausing of RNA polymerase II
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2018-06-26
Date Acceptance
2018-05-30
Citation
Cell Reports, 2018, 23 (13), pp.3933-3945
ISSN
2211-1247
Publisher
Elsevier
Start Page
3933
End Page
3945
Journal / Book Title
Cell Reports
Volume
23
Issue
13
Copyright Statement
© 2018 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
http://dx.doi.org/10.1016/j.celrep.2018.05.097
Publication Status
Published
Date Publish Online
2018-06-26