Abstract
BackgroundGene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters. Our current understanding of the influence of distal DNA methylation changes on gene expression patterns is incomplete. Here, we characterize genome-wide methylation and expression patterns for ~ 13 k genes to explore how DNA methylation interacts with gene expression, throughout the genome.ResultsWe used a linear mixed model framework to assess the correlation of DNA methylation at ~ 400 k CpGs with gene expression changes at ~ 13 k transcripts in two independent datasets from human blood cells. Among CpGs at which methylation significantly associates with transcription (eCpGs), > 50% are distal (> 50 kb) or trans (different chromosome) to the correlated gene. Many eCpG-transcript pairs are consistent between studies and ~ 90% of neighboring eCpGs associate with the same gene, within studies. We find that enhancers (P < 5e-18) and microRNA genes (P = 9e-3) are overrepresented among trans eCpGs, and insulators and long intergenic non-coding RNAs are enriched among cis and distal eCpGs. Intragenic-eCpG-transcript correlations are negative in 60–70% of occurrences and are enriched for annotated gene promoters and enhancers (P < 0.002), highlighting the importance of intragenic regulation. Gene Ontology analysis indicates that trans eCpGs are enriched for transcription factor genes and chromatin modifiers, suggesting that some trans eCpGs represent the influence of gene networks and higher-order transcriptional control.ConclusionsThis work sheds new light on the interplay between epigenetic changes and gene expression, and provides useful data for mining biologically-relevant results from epigenome-wide association studies.
Highlights
Gene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters
In the Grady Trauma Project (GTP), whole blood samples were collected from 333 participants (76% female) aged 18–78 years (GEO accession numbers GSE72680, GSE58137)
In the Multi-Ethnic Study of Atherosclerosis (MESA), relevant data were available for purified monocytes from 1202 participants (51% female) aged 55–94 years (GEO accession number GSE56047, Table 1)
Summary
Gene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters. Our current understanding of the influence of distal DNA methylation changes on gene expression patterns is incomplete. Regions of CpG-rich sequences, termed CpG islands, are found throughout the human genome. These CpG islands overlap with promoter regions or transcription factor binding sites for approximately half of mammalian genes, including most housekeeping genes [1]. Despite a growing number of EWAS, we are still far from understanding how epigenetic changes contribute to the onset of complex diseases [2, 15]. Inferring a functional consequence of such results is difficult because our understanding of the role of methylation in gene
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