| First Author | Mathur R | Year | 2017 |
| Journal | Nat Genet | Volume | 49 |
| Issue | 2 | Pages | 296-302 |
| PubMed ID | 27941798 | Mgi Jnum | J:259945 |
| Mgi Id | MGI:6141743 | Doi | 10.1038/ng.3744 |
| Citation | Mathur R, et al. (2017) ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49(2):296-302 |
| abstractText | Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in approximately 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/beta-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. |
