Letter | Published:

Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin

Nature Genetics volume 49, pages 282288 (2017) | Download Citation

Abstract

Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs)1,2,3,4,5. This opposition underlies the tumor-suppressive role of BAF subunits3,5,6,7 and is expected to contribute to neurodevelopmental disorders8,9. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF–PRC opposition underlying development and disease.

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Acknowledgements

This paper is dedicated to the memory of Joseph P. Calarco, a great friend and passionate scientist. We apologize to our colleagues whose work we could not cite owing to space constraints. We thank G. Hu, W. Jin, E. Chory, J. Bradner, and D. Hargreaves for helpful discussions and E. Miller for sharing curated GEO data sets. Arid1a conditional deletion cells were a gift from D. Hargreaves (Salk Institute). All libraries were sequenced by the DNA Sequencing and Genomics Core facility of NHLBI. Analysis was performed using the Stanford BioX3 cluster, supported by NIH S10 Shared Instrumentation Grant 1S10RR02664701. This work was also supported by the SFARI Foundation (G.R.C.), NIH grants R37NS046789 (G.R.C.) and R01CA163915 (G.R.C.), and the Division of Intramural Research, NHLBI/NIH (K.Z.). G.R.C. is an HHMI Investigator. S.M.G.B. is supported by a Swiss National Science Foundation (SNSF) postdoctoral fellowship. C.H. is supported by NCI career transition award K99CA187565.

Author information

Author notes

    • Benjamin Z Stanton
    •  & Courtney Hodges

    These authors contributed equally to this work.

Affiliations

  1. Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Benjamin Z Stanton
    • , Courtney Hodges
    • , Joseph P Calarco
    • , Simon M G Braun
    •  & Gerald R Crabtree
  2. Systems Biology Center, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Benjamin Z Stanton
    • , Wai Lim Ku
    •  & Keji Zhao
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

    • Cigall Kadoch
  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Cigall Kadoch
  5. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Gerald R Crabtree

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Contributions

B.Z.S. and C.H. designed and conducted the experiments, performed analyses, and wrote the manuscript. J.P.C., S.M.G.B., and C.K. performed experiments. W.L.K. performed analyses. K.Z. and G.R.C. designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Keji Zhao or Gerald R Crabtree.

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DOI

https://doi.org/10.1038/ng.3735

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