Letter | Published:

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

Nature Genetics volume 49, pages 296302 (2017) | Download Citation

Abstract

Genes encoding subunits of SWI/SNF (BAF) 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 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.

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Acknowledgements

We thank S. Robine (Institut Curie) for providing Vil1-CreERT2 transgenic mice, S.H. Orkin for guidance, and members of the Roberts and Orkin laboratories for discussion. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.) and R01DK081113 (R.A.S.), by a Claudia Adams Barr grant (C.W.M.R.), and by an Innovation Award from Alex's Lemonade Stand (C.W.M.R.). R.M. and A.K.S.R. were supported by US National Institutes of Health predoctoral fellowships (1F31CA199994 and 1F31CA180784). X.W. was supported by the Pathway to Independence Award from the US National Institutes of Health (K99CA197640). The Cure AT/RT Now foundation, the Avalanna Fund, the Garrett B. Smith Foundation, Miles for Mary, ALSAC/St. Jude (C.W.M.R.), and the Lind Family (R.A.S.) provided additional support. We also thank the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core and Specialized Histopathology Core, which are supported in part by NCI Cancer Center Support Grant P30CA06516.

Author information

Affiliations

  1. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Radhika Mathur
    •  & Adrianna K San Roman
  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Radhika Mathur
    • , Boris G Wilson
    • , Xiaofeng Wang
    •  & Charles W M Roberts
  3. Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

    • Burak H Alver
    •  & Peter J Park
  4. Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Adrianna K San Roman
    •  & Ramesh A Shivdasani
  5. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Agoston T Agoston
  6. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Peter J Park
    •  & Ramesh A Shivdasani
  7. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Charles W M Roberts

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Contributions

R.M., B.G.W., R.A.S., and C.W.M.R. conceived the experiments and study design. Mouse and cell line experiments were performed by R.M., A.K.S.R., X.W., and B.G.W. Histopathological analysis was conducted by A.T.A. Computational and statistical analysis was performed by B.H.A. with guidance from P.J.P. All authors contributed to data analysis and interpretation. R.M., R.A.S., and C.W.M.R. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles W M Roberts.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12.

  2. 2.

    Supplementary Data

    Full-length blots.

Excel files

  1. 1.

    Supplementary Table 1

    Whole-exome sequencing of tumors from Mx1-Cre; Arid1afl/fl mice.

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    Supplementary Table 2

    SWI/SNF binding sites in HCT116 cells.

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    Supplementary Table 3

    ChIP–qPCR data for HCT116 cells.

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    Supplementary Table 4

    RNA–seq data with GSEA for HCT116 cells.

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    Supplementary Table 5

    H3K27ac regions of enrichment with nearest genes and Gene Ontology (GO), motif, and super-enhancer analysis in HCT116 cells.

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    Supplementary Table 6

    ENCODE accession codes for HCT116 cells.

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    Supplementary Table 7

    H3K27ac regions of enrichment with nearest genes and GO, motif, and super-enhancer analysis in mouse colon epithelium.

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    Supplementary Table 8

    RNA–seq data with GSEA for mouse colon epithelium.

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DOI

https://doi.org/10.1038/ng.3744

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