ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice
Alver, Burak Han
San Roman, Adrianna K.
Wilson, Boris G.
Roberts, Charles W. M.
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CitationMathur, Radhika, Burak Han Alver, Adrianna K. San Roman, Boris G. Wilson, Xiaofeng Wang, Agoston T. Agoston, Peter J. Park, Ramesh A. Shivdasani, and Charles W. M. Roberts. 2016. “ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.” Nature genetics 49 (2): 296-302. doi:10.1038/ng.3744. http://dx.doi.org/10.1038/ng.3744.
AbstractGenes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers1–2. 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/β-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) 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.
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