Unknown

Dataset Information

0

ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.


ABSTRACT: Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in ?20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/?-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A.

SUBMITTER: Mathur R 

PROVIDER: S-EPMC5285448 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC3954704 | BioStudies
2016-11-21 | GSE71513 | GEO
2016-11-21 | GSE71512 | GEO
2018-01-01 | S-EPMC6032401 | BioStudies
2016-11-21 | GSE71511 | GEO
2016-11-21 | GSE71510 | GEO
2017-01-01 | S-EPMC5643100 | BioStudies
2018-01-01 | S-EPMC6146183 | BioStudies
2020-01-01 | S-EPMC7439613 | BioStudies
2013-01-01 | S-EPMC3552954 | BioStudies