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Dynamics of BAF–Polycomb complex opposition on heterochromatin in normal and oncogenic states

Nature Genetics volume 49, pages 213222 (2017) | Download Citation

Abstract

The opposition between Polycomb repressive complexes (PRCs) and BAF (mSWI/SNF) complexes has a critical role in both development and disease. Mutations in the genes encoding BAF subunits contribute to more than 20% of human malignancies, yet the underlying mechanisms remain unclear, owing largely to a lack of assays to assess BAF function in living cells. To address this, we have developed a widely applicable recruitment assay system through which we find that BAF opposes PRC by rapid, ATP-dependent eviction, leading to the formation of accessible chromatin. The reversal of this process results in reassembly of facultative heterochromatin. Surprisingly, BAF-mediated PRC eviction occurs in the absence of RNA polymerase II (Pol II) occupancy, transcription, and replication. Further, we find that tumor-suppressor and oncogenic mutant BAF complexes have different effects on PRC eviction. The results of these studies define a mechanistic sequence underlying the resolution and formation of facultative heterochromatin, and they demonstrate that BAF opposes PRC on a minute-by-minute basis to provide epigenetic plasticity.

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Acknowledgements

We would like to dedicate this paper to Joe Calarco, who died tragically during the course of this work. His energy, enthusiasm, and insight will continue to guide our work and his warmth brightens our memories.

We are grateful to N. Hathaway, O. Bell, L. Chen, and J. Ronan, for insightful comments and technical assistance. We thank M. Alhamadsheh for synthesis of FK1012. We also thank J. Buenrostro and B. Wu for helpful advice and technical assistance with accessibility studies and V. Petkova. C.K. was supported by the NIH Director's New Innovator Award DP2 (1DP2CA195762-01), the American Cancer Society Scholar Award (RSG-14-051-01-DMC), the Pew Scholar Award, the A.P. Giannini Foundation, the Alex's Lemonade Stand Foundation (ALSF) Young Investigator Award, and the NIH SARC Sarcoma SPORE Career Development and SPORE Project (5U54 CA168512-04) awards. G.R.C. is supported by NIH grants (CA163915, NS046789), CIRM RB4-05886, SFARI and the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

    • Cigall Kadoch
    • , Robert T Williams
    •  & John L Pulice
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Cigall Kadoch
    •  & John L Pulice
  3. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Joseph P Calarco
    • , Erik L Miller
    • , Christopher M Weber
    • , Simon M G Braun
    • , Emma J Chory
    •  & Gerald R Crabtree
  4. Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Joseph P Calarco
    • , Erik L Miller
    • , Christopher M Weber
    • , Simon M G Braun
    • , Emma J Chory
    •  & Gerald R Crabtree

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Contributions

C.K. and G.R.C. conceived of the study and wrote the paper. C.K., R.T.W., J.P.C., C.M.W., E.L.M., S.M.G.B., and E.J.C. planned and performed the experiments. J.L.P. performed data analysis and statistics.

Competing interests

C.K. and G.R.C. are scientific co-founders, shareholders, and consultants of Foghorn Therapeutics, Inc.

Corresponding authors

Correspondence to Cigall Kadoch or Gerald R Crabtree.

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https://doi.org/10.1038/ng.3734

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