Heterogeneous DNA methylation contributes to tumorigenesis through inducing the loss of coexpression connectivity in colorectal cancer

Abstract

Increasing evidence indicates the high heterogeneity of cancer cells. Recent studies have revealed distinct subtypes of DNA methylation in colorectal cancer (CRC); however, the mechanism of heterogeneous methylation remains poorly understood. Gene expression is a natural, intermediate quantitative trait that bridges genotypic and phenotypic features. In this work, we studied the role of heterogeneous DNA methylation in tumorigenesis via gene expression analyses. Specifically, we integrated methylation and expression data in normal and tumor tissues, and examined the perturbations in coexpression patterns. We found that the heterogeneity of methylation leads to significant loss of coexpression connectivity in CRC; this finding was validated in an independent cohort. Functional analyses showed that the lost coexpression partners participate in important cancer-related pathways/networks, such as ErbB and mitogen-activated protein kinase (MAPK) signaling pathways. Our analyses suggest that the loss of coexpression connectivity induced by methylation heterogeneity might play an important role in CRC. To our knowledge, this is the first study to interpret methylation heterogeneity in cancer from the perspective of coexpression perturbation. Our results provide new perspectives in tumor biology and may facilitate the identification of potential biomedical therapies for cancer treatment.

Methylation Status of Transcriptional Modulatory Genes Associated with Colorectal Cancer in Northeast China

“…Nevertheless, a hypothesis that heterogeneous methylation may be a “passenger” that interferes with transcription processes has been proposed, 16 and heterogeneous methylation may play an important role in tumour development 25 through perturbing the transcriptome in CRC. 37 …”

Linkage disequilibrium analysis of allelic heterogeneity in DNA methylation

“…The methylation heterogeneity (intermediate methylation 1 or partially methylated domain 2 ) is reported in primordial germ cells under epigenetic reprogramming, 3 sperms, 4 embryonic stem cells, 5 induced pluripotent stem cells, 6 placental cells, 2 and other somatic cells under normal and disease conditions. [7][8][9] These regions are highly gene enriched and often interact with other epigenetic markers such as histone modifications. 1 In embryonic stem cells, allelic heterogeneity is involved in maintaining the bimodal states of gene expression.…”

“…5 Furthermore, allelic heterogeneity is frequently found in various types of cancer cells, and the possible relationship with aberrant gene expression in cancer cells is of particular interest. 9 While previous studies have defined allelic heterogeneity based mainly on the methylation levels of individual CpG sites, the underlying methylation pattern within each allele has not yet been examined. Accordingly, it is important to determine the linear methylation pattern of consecutive CpG sites within each allele.…”

Heterogeneous pattern of DNA methylation in developmentally important genes correlates with its chromatin conformation

“…It has also been reported that the methylation patterns present in several imprinted genes and repetitive elements of embryonic germ (EG) cells may exhibit DNA methylation changes occurring in the germ cell lineage during the differentiation process [32]. Induction of mosaic DNA methylation patterns also leads to tumorigenesis by participating in important cancer related pathways and thus causing loss of co-expression connectivity in colorectal cancer [33]. The presence of epigenetic heterogeneity of developmentally important genes has important implications for assisted reproduction outcomes [34].…”