The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts

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.

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

“…33 In this study, 10% of the DM CpGs were significantly correlated with the gene expression. This figure is similar to previous genome-wide studies in primary fibroblast samples (8.9%), 34 ductal carcinoma in situ (DCIS) of the breast (10.5%) 35 and considerably higher than other studies in breast tumors (The Cancer Genome Atlas (TCGA) breast cancer data set) (3.3%) (35). Taken together, these data suggest that associations of methylation to gene expression vary by tissue type.…”

Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass

“…and CCL5) were also differentially expressed within-pairs, and showed that the relationships between gene body or promoter methylation and gene expression are widespread, as previously reported (Wagner et al, 2014). ABCA1, CCL5 and FASLG have been previously shown to associate with HRT and menopause (Christodoulakos et al, 2007;Darabi, Rabbani et al, 2011;Kangas et al, 2014), and both UHRF1 and PPP2R2B…”

DNA methylation and healthy human aging

“…Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al ., 2007; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al ., 2009; Gutierrez Arcelus et al ., 2013).…”