SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex1,2, is inactivated in nearly all pediatric rhabdoid tumors3,4,5. These aggressive cancers are among the most genomically stable6,7,8, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting—markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.
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Gene Expression Omnibus
We thank members of the Roberts and Park laboratories for assistance and discussion. We thank J. Francois (Boston Children's Hospital), J. Roth (Children's Hospital of Philadelphia), M. Lear (St. Jude Children's Research Hospital), and J. Silterra (Broad Institute) for their help in acquiring and performing preliminary clinical analysis of primary tumor samples; R. Rubio (Dana-Farber Cancer Institute) and M. Uziel (Broad Institute) for their assistance in sequencing samples; N. Shoresh (Broad Institute) for assistance in accessing Roadmap Epigenomics data; and R. Tomaino (Harvard Medical School) for assistance in proteomic analysis. X.W. was supported by the Pathway to Independence Award from the US National Institutes of Health (K99CA197640), a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research and The Truth 365, and a research grant from St. Baldrick's Foundation. R.S.L. was partially supported by an NSF Graduate Research Fellowship. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.), R01CA113794 (C.W.M.R.), and U54HG006991 (B.E.B.). The Avalanna Fund, the Cure AT/RT Now Foundation, the Garrett B. Smith Foundation, Miles for Mary, and ALSAC/St. Jude (C.W.M.R.) provided additional support.
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