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 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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Figure 1: ARID1A loss drives invasive colon adenocarcinoma in mice.
Figure 2: ARID1A loss drives colon tumorigenesis independent of APC inactivation.
Figure 3: ARID1A loss causes defects in SWI/SNF targeting to chromatin.
Figure 4: SWI/SNF complexes are targeted to enhancers and contribute to their activity.
Figure 5: ARID1A loss impairs enhancer-mediated gene regulation in the colonic epithelium.
Figure 6

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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.

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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.

Corresponding author

Correspondence to Charles W M Roberts.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12. (PDF 8381 kb)

Supplementary Table 1

Whole-exome sequencing of tumors from Mx1-Cre; Arid1afl/fl mice. (XLSX 245 kb)

Supplementary Table 2

SWI/SNF binding sites in HCT116 cells. (XLSX 861 kb)

Supplementary Table 3

ChIP–qPCR data for HCT116 cells. (XLSX 45 kb)

Supplementary Table 4

RNA–seq data with GSEA for HCT116 cells. (XLSX 3833 kb)

Supplementary Table 5

H3K27ac regions of enrichment with nearest genes and Gene Ontology (GO), motif, and super-enhancer analysis in HCT116 cells. (XLSX 4412 kb)

Supplementary Table 6

ENCODE accession codes for HCT116 cells. (XLSX 40 kb)

Supplementary Table 7

H3K27ac regions of enrichment with nearest genes and GO, motif, and super-enhancer analysis in mouse colon epithelium. (XLSX 5256 kb)

Supplementary Table 8

RNA–seq data with GSEA for mouse colon epithelium. (XLSX 3115 kb)

Supplementary Data

Full-length blots. (PDF 1109 kb)

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Mathur, R., Alver, B., San Roman, A. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49, 296–302 (2017). https://doi.org/10.1038/ng.3744

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