Homeobox Oncogene Activation by Pan-cancer DNA Hypermethylation

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2018 Aug 12

PMID 30097071

Citations 58

Authors

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

Affiliations

Soon will be listed here.

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.

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