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

Abstract

Background: DNA 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. Results: Here 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. Conclusion: Our 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.

Genome-wide methylation analysis identified sexually dimorphic methylated regions in hybrid tilapia

“…Gene suppression effect is most robust when the CpG methylation level in the corresponding promoter region is high. This finding is consistent with reported vertebrate methylomes such as human peripheral blood mononuclear cells (PBMCs), mice and tetraodon fish46. Our data extends the conventional view that promoter CpG methylation in teleost genomes can suppress gene expression, similar to the observations found in mammalian genomes.…”

Body-hypomethylated human genes harbor extensive intragenic transcriptional activity and are prone to cancer-associated dysregulation

“…The rest of human genes are referred to as ‘ other genes ’ henceforth. Consistent with previous studies (8,34,42), methylation levels of promoters are not necessarily correlated with those of gene bodies, and hypomethylated genes show high heterogeneity of promoter methylation levels (Supplementary Figure S1). …”

Sexual epigenetics: gender-specific methylation of a gene in the sex determining region of Populus balsamifera

“…The concentration of methylation at the 5-prime end of the gene is consistent with control regions generally being found in the first intron19 and 5-prime to the gene (promoter region). In Arabidopsis only about 5% of expressed genes are methylated at the proximal promoter2021, but promoter methylation is well known to influence transcription22.…”