DNA co-methylation has a stable structure and is related to specific aspects of genome regulation

Abstract

DNA methylation (DNAm) is influenced by genetic and environmental factors, and can be used to understand interindividual variability in genomic regulation. Co-methylation between DNAm sites is a known phenomenon, but the architecture of relationships between the approximately 450,000 (450k) sites commonly measured in epidemiological studies has not been described. We investigate whether interindividual co-methylation structure amongst the 450k sites changes with age, whether it differs between UK-born White (n=849, 910, 921 and 424) and Pakistani ancestry (n=439) individuals, and how it relates to genome regulation. We find stability between birth and adolescence, across cohorts, and between two ethnic groups. Highly correlated DNAm sites in close proximity are heritable, but these relationships are weakly influenced by nearby genetic variants, and are enriched for transcription factor (TF) binding sites related to regulation of short RNAs transcribed by RNA polymerase III. Highly correlated sites that are distant, or on different chromosomes (in trans), are driven by common and unique environmental factors, with methylation at these sites less likely to be driven by genotype. Trans co-methylated DNAm sites are enriched for multiple TF binding sites and for inter-chromosomal chromatin contact sites, suggesting DNA co-methylation of distant sites may relate to long-range cooperative TF interactions. We conclude that DNA co-methylation has a stable structure from birth to adolescence, and between UK-born White and Pakistani individuals. This stable structure might have implications for future design and interpretation of epigenetic studies. We hypothesise that co-methylation may have roles in genome regulation in humans, including 3D chromatin architecture.