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Homeobox oncogene activation by pan-cancer DNA hypermethylation

BACKGROUND: Cancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce...

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Autores principales: Su, Jianzhong, Huang, Yung-Hsin, Cui, Xiaodong, Wang, Xinyu, Zhang, Xiaotian, Lei, Yong, Xu, Jianfeng, Lin, Xueqiu, Chen, Kaifu, Lv, Jie, Goodell, Margaret A., Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085761/
https://www.ncbi.nlm.nih.gov/pubmed/30097071
http://dx.doi.org/10.1186/s13059-018-1492-3
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author Su, Jianzhong
Huang, Yung-Hsin
Cui, Xiaodong
Wang, Xinyu
Zhang, Xiaotian
Lei, Yong
Xu, Jianfeng
Lin, Xueqiu
Chen, Kaifu
Lv, Jie
Goodell, Margaret A.
Li, Wei
author_facet Su, Jianzhong
Huang, Yung-Hsin
Cui, Xiaodong
Wang, Xinyu
Zhang, Xiaotian
Lei, Yong
Xu, Jianfeng
Lin, Xueqiu
Chen, Kaifu
Lv, Jie
Goodell, Margaret A.
Li, Wei
author_sort Su, Jianzhong
collection PubMed
description BACKGROUND: Cancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce oncogene expression remains unknown. RESULTS: Here, through pan-cancer analysis of 4174 genome-wide profiles, including whole-genome bisulfite sequencing data from 30 normal tissues and 35 solid tumors, we discover a strong correlation between gene-body hypermethylation of DNA methylation canyons, defined as broad under-methylated regions, and overexpression of approximately 43% of homeobox genes, many of which are also oncogenes. To gain insights into the cause-and-effect relationship, we use a newly developed dCas9-SunTag-DNMT3A system to methylate genomic sites of interest. The locus-specific hypermethylation of gene-body canyon, but not promoter, of homeobox oncogene DLX1, can directly increase its gene expression. CONCLUSIONS: Our pan-cancer analysis followed by functional validation reveals DNA hypermethylation as a novel epigenetic mechanism for homeobox oncogene upregulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-018-1492-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-60857612018-08-16 Homeobox oncogene activation by pan-cancer DNA hypermethylation Su, Jianzhong Huang, Yung-Hsin Cui, Xiaodong Wang, Xinyu Zhang, Xiaotian Lei, Yong Xu, Jianfeng Lin, Xueqiu Chen, Kaifu Lv, Jie Goodell, Margaret A. Li, Wei Genome Biol Research BACKGROUND: Cancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce oncogene expression remains unknown. RESULTS: Here, through pan-cancer analysis of 4174 genome-wide profiles, including whole-genome bisulfite sequencing data from 30 normal tissues and 35 solid tumors, we discover a strong correlation between gene-body hypermethylation of DNA methylation canyons, defined as broad under-methylated regions, and overexpression of approximately 43% of homeobox genes, many of which are also oncogenes. To gain insights into the cause-and-effect relationship, we use a newly developed dCas9-SunTag-DNMT3A system to methylate genomic sites of interest. The locus-specific hypermethylation of gene-body canyon, but not promoter, of homeobox oncogene DLX1, can directly increase its gene expression. CONCLUSIONS: Our pan-cancer analysis followed by functional validation reveals DNA hypermethylation as a novel epigenetic mechanism for homeobox oncogene upregulation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-018-1492-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-10 /pmc/articles/PMC6085761/ /pubmed/30097071 http://dx.doi.org/10.1186/s13059-018-1492-3 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
Su, Jianzhong
Huang, Yung-Hsin
Cui, Xiaodong
Wang, Xinyu
Zhang, Xiaotian
Lei, Yong
Xu, Jianfeng
Lin, Xueqiu
Chen, Kaifu
Lv, Jie
Goodell, Margaret A.
Li, Wei
Homeobox oncogene activation by pan-cancer DNA hypermethylation
title Homeobox oncogene activation by pan-cancer DNA hypermethylation
title_full Homeobox oncogene activation by pan-cancer DNA hypermethylation
title_fullStr Homeobox oncogene activation by pan-cancer DNA hypermethylation
title_full_unstemmed Homeobox oncogene activation by pan-cancer DNA hypermethylation
title_short Homeobox oncogene activation by pan-cancer DNA hypermethylation
title_sort homeobox oncogene activation by pan-cancer dna hypermethylation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085761/
https://www.ncbi.nlm.nih.gov/pubmed/30097071
http://dx.doi.org/10.1186/s13059-018-1492-3
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