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Nat Genet. 2017 Feb;49(2):282-288. doi: 10.1038/ng.3735. Epub 2016 Dec 12.

Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin.

Author information

1
Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
2
Systems Biology Center, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
4
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
5
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

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). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. 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.

PMID:
27941795
PMCID:
PMC5373480
DOI:
10.1038/ng.3735
[Indexed for MEDLINE]
Free PMC Article

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