Pan-Cancer Genome-Wide DNA Methylation Analyses Revealed That Hypermethylation Influences 3D Architecture and Gene Expression Dysregulation in HOXA Locus During Carcinogenesis of Cancers.

Gang Liu,Yunhe Liu,Lei Liu,Xiaoqiong Xia,Xiaomeng Sun,Zhenhao Liu

doi:10.3389/fcell.2021.649168

Abstract

DNA methylation dysregulation during carcinogenesis has been widely discussed in recent years. However, the pan-cancer DNA methylation biomarkers and corresponding biological mechanisms were seldom investigated. We identified differentially methylated sites and regions from 5,056 The Cancer Genome Atlas (TCGA) samples across 10 cancer types and then validated the findings using 48 manually annotated datasets consisting of 3,394 samples across nine cancer types from Gene Expression Omnibus (GEO). All samples’ DNA methylation profile was evaluated with Illumina 450K microarray to narrow down the batch effect. Nine regions were identified as commonly differentially methylated regions across cancers in TCGA and GEO cohorts. Among these regions, a DNA fragment consisting of ∼1,400 bp detected inside the HOXA locus instead of the boundary may relate to the co-expression attenuation of genes inside the locus during carcinogenesis. We further analyzed the 3D DNA interaction profile by the publicly accessible Hi-C database. Consistently, the HOXA locus in normal cell lines compromised isolated topological domains while merging to the domain nearby in cancer cell lines. In conclusion, the dysregulation of the HOXA locus provides a novel insight into pan-cancer carcinogenesis.

Highlights

Aberrant DNA methylation during carcinogenesis has been studied for a long period in the past decades
We found that HOXA locus DNA hypermethylation is a commonly shared signature across cancers
All DNA methylation datasets evaluated by Illumina Human Methylation 450K BeadChip in The Cancer Genome Atlas (TCGA) cohorts were used in this study

Summary

Introduction

Aberrant DNA methylation during carcinogenesis has been studied for a long period in the past decades. The roles of DNA methylation during carcinogenesis are complex (Patai et al, 2012; Moore et al, 2013; Duruisseaux and Esteller, 2018). A study revealed that gene body DNA methylation systematically enhanced gene expression, as hypermethylation in promoter regions inhibited transcription factor binding and silenced specific genes (Yang et al, 2014). Intergenic DNA methylation influences spurious transcription initiation (Neri et al, 2017). HOXA Locus Hypermethylation Across Cancers methylation in nuclear territories could transform euchromatin into heterochromatin and inhibit gene activation (Bártová and Kozubek, 2006). In addition to gene suppression, some studies revealed that promoter DNA methylation recruited specific transcription factors and promoted gene expression (Qiu et al, 2016)

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