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

HC. Hodges, BZ. Stanton, K. Cermakova, CY. Chang, EL. Miller, JG. Kirkland, WL. Ku, V. Veverka, K. Zhao, GR. Crabtree,

. 2018 ; 25 (1) : 61-72. [pub] 20171211

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19035447

Grant support
R00 CA187565 NCI NIH HHS - United States
T32 CA009151 NCI NIH HHS - United States
R37 NS046789 NINDS NIH HHS - United States
Howard Hughes Medical Institute - United States
R01 CA163915 NCI NIH HHS - United States

E-resources Online Full text

NLK ProQuest Central from 2004-01-01 to 1 year ago
Health & Medicine (ProQuest) from 2004-01-01 to 1 year ago

Links

PubMed 29323272
DOI 10.1038/s41594-017-0007-3
Knihovny.cz E-resources

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.

References provided by Crossref.org

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$a Stanton, Benjamin Z $u Departments of Pathology, Genetics, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. Systems Biology Center, Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
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$a Chang, Chiung-Ying $u Departments of Pathology, Genetics, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
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$a Crabtree, Gerald R $u Departments of Pathology, Genetics, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. crabtree@stanford.edu. Howard Hughes Medical Institute, Chevy Chase, MD, USA. crabtree@stanford.edu.
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