Abstract
BackgroundDNA methylation plays an essential role in the regulation of gene expression. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood.ResultsWe report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5 kb. Via eQTL analysis with microarray data combined with mapping of allelic expression regions, we obtained a set of 2,770 regions mappable in cis to sequence variation. In 9.5% of these expressed regions, an associated SNP was also a methylation QTL. Methylation and gene expression are often correlated without direct discernible involvement of sequence variation, but not always in the expected direction of negative for promoter CpGs and positive for gene-body CpGs. Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific chromatin marks rather than position of the CpG site with respect to the gene.ConclusionsOur results indicate a wide variety of relationships between gene expression, DNA methylation and sequence variation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and some discernible involvement of sequence variation.
Highlights
DNA methylation plays an essential role in the regulation of gene expression
We report on the joint analysis of inter-individual variation in the levels of DNA methylation, total and allelic expression, and DNA sequence of 62 healthy parents of 31 parent-child trios of European descent
Methylation was measured at approximately 485,000 CpG sites, but we only considered the approximately 392,000 sites uniquely mapped in autosomes and containing no known SNPs
Summary
DNA methylation plays an essential role in the regulation of gene expression. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. Zhang et al [14] performed similar analyses using the same methylation platform in 153 human adult cerebellum samples, finding 2,046 CpG sites with mQTLs; they reported that, in general, CpG sites located in CpG islands are more likely to be mappable to a SNP than non-CpG island sites. They assessed the relationship between expression and methylation, with 20 of 112 CpG-gene pairs analyzed showing nominally significant correlations, with 5 of these 20 being positive correlations and the rest negative. Gutierrez-Arcelus et al [17] report positive and negative expression-methylation relationships at the interindividual level in fibroblasts, T cells and LCLs derived from a set of 204 umbilical cords from healthy newborns of European descent, with negatively correlated CpG sites enriched at ENCODE derived enhancer and promoter sites
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
