Summary
DNA methylation dynamics is intrinsically interconnected with processes underlying the malignant properties of cancer cells. By applying network-based approaches in two series of colorectal cancers we dissected the long-range co-methylation structure finding consistent patterns of compartmentalization in both normal and tumor tissues. Large transchromosomal modules showed unique regulatory signatures and coalesced into a structured network and allowing simple patient stratification. Normal-tumor comparison revealed substantial remodeling of specific modules and migration of subsets of co-methylating sites denoted by functional aggregates, pointing out potential sources of epigenetic and phenotypic variability. We conclude that DNA methylation dynamics architecture embodies interpretable information that can be used as a proxy of the drivers and the phenotypes of malignant transformation.
Significance DNA methylation is a key epigenetic mark directly involved in genome organization and regulation. DNA methylation profiles are variable and are extensively altered in most cancers. We show that DNA methylation variability follows a transchromosomal modular dynamics in both normal and colon cancer cells. The reshaping of the DNA methylation variability network in tumorigenesis exposes genomic and functional associations and points out both the mechanisms and the phenotypes of individual tumors. This information may be used for patient stratification and identification of disrupted pathways and therapeutic targets.
Highlights
DNA methylation variability displays a modular architecture in normal and cancer.
Coordinated transchromosomal variations supersede regional DNA methylation dynamics.
Co-methylation network modularity evinces functional and structural features.
Epigenetic rewiring can be used as patient stratifier.
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