GSE54373
The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts [Whole genome bisulfite sequencing]
Background DNA methylation has long been known to play an essential role in the epigenetic regulation of gene expression and other cellular functions, and has been in some cases linked to genetic variation. 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.  Results We 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 5kb. However, only 5% of those mappable CpG sites also have methylation levels that correlate in cis with a gene''s expression level. Methylation and gene expression are often correlated but not always in the expected direction (negative for promoter CpGs, 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 histone marks or DNase hypersensitivity rather than position of the CpG site with respect to the gene, showing that other epigenetic markers are necessary to interpret downstream effects of individual methylation variants.  Conclusion Our results indicate strong relationships between gene expression and DNA methylation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and relatively modest involvement of sequence variation. Overall design: Four human skin fibroblast samples obtained from Coriell. Bisulfite converted DNA was sequenced using the Illumina HiSeq 2000 system.