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Genome Biol. 2018 Aug 10;19(1):108. doi: 10.1186/s13059-018-1492-3.

Homeobox oncogene activation by pan-cancer DNA hypermethylation.

Author information

1
School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325011, Zhejiang, China. sujz@wibe.ac.cn.
2
Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. sujz@wibe.ac.cn.
3
Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Sciences, Wenzhou, 325000, China. sujz@wibe.ac.cn.
4
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA.
5
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
6
Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
7
School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325011, Zhejiang, China.
8
Center for Epigenetics, Van Andel Research Institution, Grand Rapids, MI, 49503, USA.
9
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA. goodell@bcm.edu.
10
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. goodell@bcm.edu.
11
Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. WL1@bcm.edu.

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

PMID:
30097071
PMCID:
PMC6085761
DOI:
10.1186/s13059-018-1492-3
[Indexed for MEDLINE]
Free PMC Article

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