Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00489776" target="_blank" >RIV/61388963:_____/18:00489776 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.1038/s41594-017-0007-3" target="_blank" >http://dx.doi.org/10.1038/s41594-017-0007-3</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41594-017-0007-3" target="_blank" >10.1038/s41594-017-0007-3</a>
Alternative languages
Result language
angličtina
Original language name
Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GA16-06357S" target="_blank" >GA16-06357S: Structural basis for the biological function of LEDGF/p75 and HRP-2</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Nature structural & molecular biology
ISSN
1545-9993
e-ISSN
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Volume of the periodical
25
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
61-72
UT code for WoS article
000423547700010
EID of the result in the Scopus database
2-s2.0-85042743313