Homeobox oncogene activation by pan-cancer DNA hypermethylation

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

Research output: Contribution to journalArticle

25 Scopus citations

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.

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

Keywords

  • DNA methylation
  • Gene-body
  • Homeobox oncogene
  • Hypermethylation
  • Methylation editing
  • Pan-cancer analysis
  • Transcription
  • Whole-genome bisulfite sequencing

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Fingerprint Dive into the research topics of 'Homeobox oncogene activation by pan-cancer DNA hypermethylation'. Together they form a unique fingerprint.

  • Cite this

    Su, J., Huang, Y. H., Cui, X., Wang, X., Zhang, X., Lei, Y., Xu, J., Lin, X., Chen, K., Lv, J., Goodell, M. A., & 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