Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer

BACKGROUND: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations fr...

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Autores principales: Yang, Jiekun, Wei, Xiaolong, Tufan, Turan, Kuscu, Cem, Unlu, Hayrunnisa, Farooq, Saadia, Demirtas, Elif, Paschal, Bryce M., Adli, Mazhar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223090/
https://www.ncbi.nlm.nih.gov/pubmed/30404658
http://dx.doi.org/10.1186/s13059-018-1572-4
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author Yang, Jiekun
Wei, Xiaolong
Tufan, Turan
Kuscu, Cem
Unlu, Hayrunnisa
Farooq, Saadia
Demirtas, Elif
Paschal, Bryce M.
Adli, Mazhar
author_facet Yang, Jiekun
Wei, Xiaolong
Tufan, Turan
Kuscu, Cem
Unlu, Hayrunnisa
Farooq, Saadia
Demirtas, Elif
Paschal, Bryce M.
Adli, Mazhar
author_sort Yang, Jiekun
collection PubMed
description BACKGROUND: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. RESULTS: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. CONCLUSIONS: Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-018-1572-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-62230902018-11-19 Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer Yang, Jiekun Wei, Xiaolong Tufan, Turan Kuscu, Cem Unlu, Hayrunnisa Farooq, Saadia Demirtas, Elif Paschal, Bryce M. Adli, Mazhar Genome Biol Research BACKGROUND: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. RESULTS: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. CONCLUSIONS: Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-018-1572-4) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-07 /pmc/articles/PMC6223090/ /pubmed/30404658 http://dx.doi.org/10.1186/s13059-018-1572-4 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Yang, Jiekun
Wei, Xiaolong
Tufan, Turan
Kuscu, Cem
Unlu, Hayrunnisa
Farooq, Saadia
Demirtas, Elif
Paschal, Bryce M.
Adli, Mazhar
Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title_full Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title_fullStr Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title_full_unstemmed Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title_short Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
title_sort recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223090/
https://www.ncbi.nlm.nih.gov/pubmed/30404658
http://dx.doi.org/10.1186/s13059-018-1572-4
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