On the presence and role of human gene-body DNA methylation
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Date
2012
Journal Title
Journal ISSN
Volume Title
Publisher
Oncotarget
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.
Description
Keywords
Genome-wide methylation, Epigenetic mark, Intragenic transcription, Methylating enzyme complexes
Citation
Jjingo, D., Conley, A. B., Soojin, V. Y., Lunyak, V. V., & Jordan, I. K. (2012). On the presence and role of human gene-body DNA methylation. Oncotarget, 3(4), 462.