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

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...

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Autores principales: Hodges, H. Courtney, Stanton, Benjamin Z., Cermakova, Katerina, Chang, Chiung-Ying, Miller, Erik L., Kirkland, Jacob G., Ku, Wai Lim, Veverka, Vaclav, Zhao, Keji, Crabtree, Gerald R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909405/
https://www.ncbi.nlm.nih.gov/pubmed/29323272
http://dx.doi.org/10.1038/s41594-017-0007-3
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author Hodges, H. Courtney
Stanton, Benjamin Z.
Cermakova, Katerina
Chang, Chiung-Ying
Miller, Erik L.
Kirkland, Jacob G.
Ku, Wai Lim
Veverka, Vaclav
Zhao, Keji
Crabtree, Gerald R.
author_facet Hodges, H. Courtney
Stanton, Benjamin Z.
Cermakova, Katerina
Chang, Chiung-Ying
Miller, Erik L.
Kirkland, Jacob G.
Ku, Wai Lim
Veverka, Vaclav
Zhao, Keji
Crabtree, Gerald R.
author_sort Hodges, H. Courtney
collection PubMed
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 induced 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 SMARCA4-mutated disorders in a wide variety of tissues.
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spelling pubmed-59094052018-06-11 Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers Hodges, H. Courtney Stanton, Benjamin Z. Cermakova, Katerina Chang, Chiung-Ying Miller, Erik L. Kirkland, Jacob G. Ku, Wai Lim Veverka, Vaclav Zhao, Keji Crabtree, Gerald R. Nat Struct Mol Biol Article 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 induced 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 SMARCA4-mutated disorders in a wide variety of tissues. 2017-12-11 2018-01 /pmc/articles/PMC5909405/ /pubmed/29323272 http://dx.doi.org/10.1038/s41594-017-0007-3 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Hodges, H. Courtney
Stanton, Benjamin Z.
Cermakova, Katerina
Chang, Chiung-Ying
Miller, Erik L.
Kirkland, Jacob G.
Ku, Wai Lim
Veverka, Vaclav
Zhao, Keji
Crabtree, Gerald R.
Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title_full Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title_fullStr Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title_full_unstemmed Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title_short Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
title_sort dominant-negative smarca4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909405/
https://www.ncbi.nlm.nih.gov/pubmed/29323272
http://dx.doi.org/10.1038/s41594-017-0007-3
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