On the presence and role of human gene-body DNA methylation

Abstract

ABSTRACT:DNA methylation of promoter sequences is a repressive epigenetic mark that down-regulates gene expression. However, DNA methylation is more prevalent within gene-bodies than seen for promoters, and gene-body methylation has been observed to be positively correlated with gene expression levels. This paradox remains unexplained, and accordingly the role of DNA methylation in gene-bodies is poorly understood. We addressed the presence and role of human gene-body DNA methylation using a meta-analysis of human genome-wide methylation, expression and chromatin data sets. Methylation is associated with transcribed regions as genic sequences have higher levels of methylation than intergenic or promoter sequences. We also find that the relationship between gene-body DNA methylation and expression levels is non-monotonic and bell-shaped. Mid-level expressed genes have the highest levels of gene-body methylation, whereas the most lowly and highly expressed sets of genes both have low levels of methylation.While gene-body methylation can be seen to efficiently repress the initiation of intragenic transcription, the vast majority of methylated sites within genes are not associated with intragenic promoters. In fact, highly expressed genes initiate the most intragenic transcription, which is inconsistent with the previously held notion that gene-body methylation serves to repress spurious intragenic transcription to allow for efficient transcriptional elongation. These observations lead us to propose a model to explain the presence of human gene-body methylation. This model holds that the repression of intragenic transcription by gene-body methylation is largely epiphenomenal, and suggests that gene-body methylation levels are predominantly shaped via the accessibility of the DNA to methylating enzyme complexes.

DNA methylation and evolution of duplicate genes

“…This observation is in accord with previous studies that find consistently high methylation in mammalian gene bodies (34,35). A recent study in rice, however, found that gene-body methylation and divergence is associated with their evolutionary age (36).…”

High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines

“…13 Recent literature, however, suggests that body methylation may play an equally important role in controlling gene expression. 17,18 Less than 1% of the promoter and body CpG sites represented on the BeadChip are hypermethylated in both TMX2-11 and TMX2-28 and of these dmCpGs, slightly more are in the body than in the promoter region (0.66% vs. 0.52%).…”

Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension

“…Gene-body methylation identified 'orphan promoters', which may be used in the early stages of development (30). Hypermethylation of gene-bodies frequently indicates higher levels of gene expression in human tissues and cell types (8,31). Aberrant methylation of the gene body was observed to contribute to the risk of heart failure (32) and coronary heart disease (23).…”

“…Gene-body methylation was found to be positively correlated with gene expression (8). Although the functions of the gene-body CpG island (CGI) remain to be elucidated, methylation of the gene-body is frequently associated with active transcription in humans and other animals (9).…”