Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R00 CA187565
NCI NIH HHS - United States
Howard Hughes Medical Institute - United States
R01 CA163915
NCI NIH HHS - United States
T32 CA009151
NCI NIH HHS - United States
R37 NS046789
NINDS NIH HHS - United States
PubMed
29323272
PubMed Central
PMC5909405
DOI
10.1038/s41594-017-0007-3
PII: 10.1038/s41594-017-0007-3
Knihovny.cz E-zdroje
- MeSH
- adenosintrifosfatasy metabolismus MeSH
- chromatin chemie MeSH
- DNA-helikasy genetika MeSH
- dominantní geny * MeSH
- epigenomika MeSH
- genotyp MeSH
- heterozygot MeSH
- jaderné proteiny genetika MeSH
- kultivační média MeSH
- lidé MeSH
- missense mutace MeSH
- multivariační analýza MeSH
- mutace * MeSH
- myší embryonální kmenové buňky cytologie MeSH
- myši transgenní MeSH
- myši MeSH
- nádory genetika MeSH
- polycomb proteiny genetika MeSH
- restrukturace chromatinu MeSH
- sekvenční analýza RNA MeSH
- transkripční faktory genetika MeSH
- zesilovače transkripce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adenosintrifosfatasy MeSH
- chromatin MeSH
- DNA-helikasy MeSH
- jaderné proteiny MeSH
- kultivační média MeSH
- polycomb proteiny MeSH
- SMARCA4 protein, human MeSH Prohlížeč
- transkripční faktory MeSH
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.
Howard Hughes Medical Institute Chevy Chase MD USA
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
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