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

Background DNA methylation (DNAm) is an epigenetic mark that can be used to understand interindividual variability in genomic regulation, and it is influenced by many genetic and environmental factors. Co-methylation between DNAm sites is a known phenomenon but the full architecture of relationships between the approximately 450,000 (450k) sites most commonly measured in epidemiological studies has not been described. We investigate whether the cis and trans interindividual co-methylation structure amongst the 450k sites changes across the lifecourse, whether it differs between UK-born White and Pakistani individuals, and how it may be related to genome regulation. Results We find stability across the life course (birth to adolescence), across cohorts, and between two ethnic groups. Highly correlated DNAm sites in close proximity are highly heritable, influenced by nearby genetic variants (cis mQTLs), and are enriched for transcription factor (TF) binding sites related to regulation of short RNAs essential for cellular function transcribed by RNA polymerase III. Highly correlated sites that are either distant, or on different chromosomes, are driven by both common and unique environmental factors, and methylation at these sites is less likely to be driven by genotype. They are enriched for a multitude of TF binding sites and for inter-chromosomal chromatin contact sites, suggesting that DNA co-methylation of distant sites may be related to long-range cooperative TF interactions. Conclusions We conclude that DNA co-methylation, especially in cis, has a stable structure from birth to adolescence and between white British and Pakistani individuals. We hypothesise that co-methylation may have roles in genome regulation in humans, including 3D chromatin architecture. The stable structure we have identified might have implications for the future design and interpretation of epigenetic studies. ### Competing Interest Statement The authors have declared no competing interest.