Homeobox oncogene activation by pan-cancer DNA hypermethylation

Research output: Contribution to journalArticle

Jianzhong Su, Yung Hsin Huang, Xiaodong Cui, Xinyu Wang, Xiaotian Zhang, Yong Lei, Jianfeng Xu, Xueqiu Lin, Kaifu Chen, Jie Lv, Margaret A. Goodell, Wei Li

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.

Original languageEnglish (US)
Article number108
JournalGenome biology
Volume19
Issue number1
DOIs
StatePublished - Aug 10 2018

PMID: 30097071

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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.

In: Genome biology, Vol. 19, No. 1, 108, 10.08.2018.

Research output: Contribution to journalArticle

Harvard

Su, J, Huang, YH, Cui, X, Wang, X, Zhang, X, Lei, Y, Xu, J, Lin, X, Chen, K, Lv, J, Goodell, MA & Li, W 2018, 'Homeobox oncogene activation by pan-cancer DNA hypermethylation' Genome biology, vol. 19, no. 1, 108. https://doi.org/10.1186/s13059-018-1492-3

APA

Su, J., Huang, Y. H., Cui, X., Wang, X., Zhang, X., Lei, Y., ... Li, W. (2018). Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome biology, 19(1), [108]. https://doi.org/10.1186/s13059-018-1492-3

Vancouver

Su J, Huang YH, Cui X, Wang X, Zhang X, Lei Y et al. Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome biology. 2018 Aug 10;19(1). 108. https://doi.org/10.1186/s13059-018-1492-3

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. / Homeobox oncogene activation by pan-cancer DNA hypermethylation. In: Genome biology. 2018 ; Vol. 19, No. 1.

BibTeX

@article{3937e4742209474ab0eec9b99621ae0b,
title = "Homeobox oncogene activation by pan-cancer DNA hypermethylation",
abstract = "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.",
keywords = "DNA methylation, Gene-body, Homeobox oncogene, Hypermethylation, Methylation editing, Pan-cancer analysis, Transcription, Whole-genome bisulfite sequencing",
author = "Jianzhong Su and Huang, {Yung Hsin} and Xiaodong Cui and Xinyu Wang and Xiaotian Zhang and Yong Lei and Jianfeng Xu and Xueqiu Lin and Kaifu Chen and Jie Lv and Goodell, {Margaret A.} and Wei Li",
year = "2018",
month = "8",
day = "10",
doi = "10.1186/s13059-018-1492-3",
language = "English (US)",
volume = "19",
journal = "Genome biology",
issn = "1474-7596",
publisher = "BioMed Central",
number = "1",

}

RIS

TY - JOUR

T1 - Homeobox oncogene activation by pan-cancer DNA hypermethylation

AU - Su, Jianzhong

AU - Huang, Yung Hsin

AU - Cui, Xiaodong

AU - Wang, Xinyu

AU - Zhang, Xiaotian

AU - Lei, Yong

AU - Xu, Jianfeng

AU - Lin, Xueqiu

AU - Chen, Kaifu

AU - Lv, Jie

AU - Goodell, Margaret A.

AU - Li, Wei

PY - 2018/8/10

Y1 - 2018/8/10

N2 - 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.

AB - 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.

KW - DNA methylation

KW - Gene-body

KW - Homeobox oncogene

KW - Hypermethylation

KW - Methylation editing

KW - Pan-cancer analysis

KW - Transcription

KW - Whole-genome bisulfite sequencing

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U2 - 10.1186/s13059-018-1492-3

DO - 10.1186/s13059-018-1492-3

M3 - Article

VL - 19

JO - Genome biology

T2 - Genome biology

JF - Genome biology

SN - 1474-7596

IS - 1

M1 - 108

ER -

ID: 40337992