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Nat Struct Mol Biol. 2018 Jan;25(1):61-72. doi: 10.1038/s41594-017-0007-3. Epub 2017 Dec 11.

Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers.

Author information

1
Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
2
Departments of Pathology, Genetics, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
3
Systems Biology Center, Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
4
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
5
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
6
Systems Biology Center, Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. zhaok@nhlbi.nih.gov.
7
Departments of Pathology, Genetics, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. crabtree@stanford.edu.
8
Howard Hughes Medical Institute, Chevy Chase, MD, USA. crabtree@stanford.edu.

Abstract

Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

PMID:
29323272
PMCID:
PMC5909405
DOI:
10.1038/s41594-017-0007-3
[Indexed for MEDLINE]
Free PMC Article

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