Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation

Abstract

BackgroundDNA methylation is an important type of epigenetic modification involved in gene regulation. Although strong DNA methylation at promoters is widely recognized to be associated with transcriptional repression, many aspects of DNA methylation remain not fully understood, including the quantitative relationships between DNA methylation and expression levels, and the individual roles of promoter and gene body methylation.ResultsHere we present an integrated analysis of whole-genome bisulfite sequencing and RNA sequencing data from human samples and cell lines. We find that while promoter methylation inversely correlates with gene expression as generally observed, the repressive effect is clear only on genes with a very high DNA methylation level. By means of statistical modeling, we find that DNA methylation is indicative of the expression class of a gene in general, but gene body methylation is a better indicator than promoter methylation. These findings are general in that a model constructed from a sample or cell line could accurately fit the unseen data from another. We further find that promoter and gene body methylation have minimal redundancy, and either one is sufficient to signify low expression. Finally, we obtain increased modeling power by integrating histone modification data with the DNA methylation data, showing that neither type of information fully subsumes the other.ConclusionOur results suggest that DNA methylation outside promoters also plays critical roles in gene regulation. Future studies on gene regulatory mechanisms and disease-associated differential methylation should pay more attention to DNA methylation at gene bodies and other non-promoter regions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0408-0) contains supplementary material, which is available to authorized users.

Linkage disequilibrium analysis of allelic heterogeneity in DNA methylation

“…In addition, the boundary between methylated and unmethylated regions often corresponds to the boundary between the gene body and intergenic regions. 16 Furthermore, gene body methylation is associated with intragenic chromatin modifications such as H3K9me3. 17 Thus, the present finding that the transitional boundary differs among alleles may indicate that the boundary of gene body methylation differs among cells, possibly depending on the degree of histone modifications and/or activity of gene expression.…”

Epigenetic regulation by DNA methylation and miRNA molecules in cancer

“…Using new techniques such as whole genome sequencing or microarray, it is possible to quantify DNA methylation in normal and cancer tissues to clarify the role of methylation in gene regulation and cancer. There is a correlation between differentially methylated regions and gene expression changes [8]. Changes in gene expression and a function of demethylating agents like azacitidine, decitabine and zebularine were studied on cell cultures.…”

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

“…Gene body methylation may positively regulate gene expression 8,9 and can be involved in splicing regulation. 8,58 However, it can also contribute to gene silencing, according to the whole genomic bisulfite and RNA sequencing data of Lou et al 59 In the recent study of Wang et al about the roles of genic methylation in prostate tumorigenesis, 12 groups of genes with collaborative differential methylation patterns, including hypermethylated promoter/hypermethylated gene body and hypermethylated promoter/hypomethylated gene body, were identified, assuming a gene activating role for gene body methylation. 60 In line with these findings, we identified strongly hypermethylated gene body associated with upregulated mRNA expression in WNT pathway genes, such as AXIN2, CSNK1E, MYC, NKD1, which expression was downregulated after 5-aza-2 0 -deoxycytidine treatment in colon cancer cell lines.…”