Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Xiaofeng Wang
    • , Ryan S Lee
    •  & Burak H Alver

    These authors contributed equally to this work.

    • Bradley E Bernstein
    • , Peter J Park
    •  & Charles W M Roberts

    These authors jointly directed this work.

Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Xiaofeng Wang
    • , Ryan S Lee
    • , Jeffrey R Haswell
    • , Jennifer N Wu
    • , Evgeni P Tzvetkov
    • , Emma C Troisi
    •  & Charles W M Roberts
  2. Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Xiaofeng Wang
    • , Ryan S Lee
    • , Jeffrey R Haswell
    • , Jennifer N Wu
    • , Evgeni P Tzvetkov
    • , Emma C Troisi
    •  & Charles W M Roberts
  3. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Xiaofeng Wang
    • , Ryan S Lee
    • , Jeffrey R Haswell
    • , Jennifer N Wu
    • , Evgeni P Tzvetkov
    • , Emma C Troisi
    •  & Charles W M Roberts
  4. Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

    • Burak H Alver
    • , Su Wang
    •  & Peter J Park
  5. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jakub Mieczkowski
    •  & Michael Y Tolstorukov
  6. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Yotam Drier
    • , Shawn M Gillespie
    •  & Bradley E Bernstein
  7. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Yotam Drier
    • , Shawn M Gillespie
    •  & Bradley E Bernstein
  8. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Tenley C Archer
    •  & Scott L Pomeroy
  9. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.

    • Jaclyn A Biegel
  10. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Bradley E Bernstein
  11. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Peter J Park
  12. Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Charles W M Roberts

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Contributions

X.W., R.S.L., B.H.A., B.E.B., P.J.P., and C.W.M.R. conceived the experiments and study design. X.W., J.R.H., E.P.T., and E.C.T. performed all cell line experiments. R.S.L. and S.M.G. performed all primary tumor experiments. B.H.A., R.S.L., S.W., J.M., and Y.D. performed computational analyses of the data. X.W., R.S.L., B.H.A., and S.W. performed statistical analyses. T.C.A., S.L.P., and J.A.B. contributed primary tumor samples and clinical data. J.N.W. designed the SMARCB1 re-expression vector. X.W., R.S.L., B.H.A., J.R.H., J.M., Y.D., M.Y.T., B.E.B., P.J.P., and C.W.M.R. contributed to the interpretation of experiments. X.W., R.S.L., B.H.A., and C.W.M.R. wrote the manuscript with input from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bradley E Bernstein or Peter J Park or Charles W M Roberts.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11.

  2. 2.

    Supplementary Data

    Full scans of blots.

Excel files

  1. 1.

    Supplementary Table 1

    Rhabdoid tumor primary GO terms.

  2. 2.

    Supplementary Table 2

    Rhabdoid tumor primary super-enhancers.

  3. 3.

    Supplementary Table 3

    Mass spectrometry.

  4. 4.

    Supplementary Table 4

    Cell line GO terms.

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DOI

https://doi.org/10.1038/ng.3746

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