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

While studies such as the 1000 Genomes Projects have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We defined sites of common 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 72 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 21 coregulated VMRs comprising all four HOX gene clusters enriched for control of tissue growth; and in neurons a network of 112 VMRs enriched for roles in learning and memory. By culturing genetically-identical fibroblasts under varying conditions of nutrient deprivation and cell density, we experimentally demonstrate that some VMR networks are responsive to environmental conditions, 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<10-94), 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.