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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2017
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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. |
format | Online Article Text |
id | pubmed-5909405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
record_format | MEDLINE/PubMed |
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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