A first-generation genome-wide map of correlated DNA methylation demonstrates highly coordinated and tissue-independent clustering across regulatory regions

Genome-wide DNA methylation studies have typically focused on quantitative assessments of CpG methylation at individual loci. Although methylation states at nearby CpG sites are known to be highly correlated, suggestive of an underlying coordinated regulatory network, the extent and consistency of inter-CpG methylation correlation across the genome, including variation between individuals, disease states, and tissues, remains unknown. Here, we leverage image conversion of correlation matrices to identify correlated methylation units (CMUs) across the genome, describe their variation across tissues, and annotate their regulatory potential using 35 public Illumina BeadChip datasets spanning more than 12,000 individuals and 26 different tissues. We identified a median of 18,125 CMUs genome-wide, occurring on all chromosomes and spanning a median of ~1 kb. Notably, 50% of CMUs had evidence of long-range correlation with other proximal CMUs. Although the size and number of CMUs varied across datasets, we observed strong intra-tissue consistency among CMUs, with those in testis encompassing those seen in most other tissues. Approximately 20% of CMUs were highly conserved across normal tissues (i.e. tissue independent), with 73 loci demonstrating strong correlation with non-adjacent CMUs on the same chromosome. These loci were enriched for CTCF and transcription factor binding sites, always found within putative TADs, and associated with the B compartment of chromosome folding. Finally, we observed significantly different, but highly consistent, patterns of CMU correlation between diseased and non-diseased states. Our first-generation, genome-wide, DNA methylation map suggests a highly coordinated CMU regulatory network that is sensitive to disruptions in its architecture.