title: 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/β-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.
authors.affiliation: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Mathur
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Burak H
authors.initials: BH
authors.lastname: Alver
authors.affiliation: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Adrianna K
authors.initials: AK
authors.lastname: San Roman
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Boris G
authors.initials: BG
authors.lastname: Wilson
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Agoston T
authors.initials: AT
authors.lastname: Agoston
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter J
authors.identifier: http://orcid.org/0000-0001-9378-960X
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ramesh A
authors.identifier: http://orcid.org/0000-0002-2828-1727
authors.initials: RA
authors.lastname: Shivdasani
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051176:beta Catenin