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Nat Genet. 2017 Feb;49(2):289-295. doi: 10.1038/ng.3746. Epub 2016 Dec 12.

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
3
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
5
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
7
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
8
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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.
10
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
11
Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
12
Comprehensive Cancer Center and Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Abstract

SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, 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.

PMID:
27941797
PMCID:
PMC5285474
DOI:
10.1038/ng.3746
[Indexed for MEDLINE]
Free PMC Article

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