A survey of inter-individual variation in DNA methylation identifies environmentally responsive co-regulated networks of epigenetic variation in the human genome

摘要

While population studies have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We identified sites containing clusters of CpGs with high inter-individual epigenetic variation, termed Variably Methylated Regions (VMRs) in five purified cell types. We observed that VMRs occur preferentially at enhancers and 3’ UTRs. While the majority of VMRs have high heritability, a subset of VMRs within the genome show highly correlated variation in trans , forming co-regulated networks that have low heritability, differ between cell types and are enriched for specific transcription factor binding sites and biological pathways of functional relevance to each tissue. For example, in T cells we defined a network of 95 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 34 co-regulated VMRs comprising all four HOX gene clusters enriched for control of tissue growth; and in neurons a network of 18 VMRs enriched for roles in synaptic signaling. By culturing genetically-identical fibroblasts under varying environmental conditions, we experimentally demonstrated that some VMR networks are responsive to the environment, with methylation levels at these loci changing in a coordinated fashion in trans dependent on cellular growth. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci (p<10~(?80)), suggesting that these are particularly sensitive to environmental conditions. Our study provides a detailed map of common epigenetic variation in the human genome, showing that both genetic and environmental causes underlie this variation. Author summary Multiple published studies have demonstrated that epigenetic variation can contribute to phenotypic variation. In the present study, we identified regions of common methylation variation in five cell types, observing that these show enrichments for functional genomic features. Surprisingly, we found that these epigenetic variations can form biologically relevant networks that are specific to each cell type, often occurring near genes that have functional relevance to the cell type. Further these regions show reduced heritability, suggesting they may be responsive to environmental cues. We confirmed this by subjecting isogenic fibroblast cultures to different environmental stress. Our study provides insight into patterns of normal epigenetic variation in the human population.