A local sequence signature defines a subset of heterochromatin-associated CpGs with minimal loss of methylation in healthy tissues but extensive loss in cancer

Abstract

Global loss of DNA methylation in mammalian genomes occurs during aging and cancer, primarily in heterochromatin-associated Partially Methylated Domains (PMDs). It has previously been shown that local sequence context (100bp) has a strong influence on the rate of demethylation of individual CpG dinucleotides within PMDs. Here, we train a deep learning model to capture this sequence dependence, finding that methylation loss in healthy tissues and cancer can be predicted with high accuracy based on the 150bp surrounding a CpG. We use a published whole-genome map of the re-methylation rate of newly synthesized DNA during mitosis to show that CpGs with a "slow-loss" sequence context are efficiently re-methylated, while CpGs with a "fast-loss" sequence context are inefficiently re-methylated. Intriguingly, we find that the 10% most slow-loss CpGs lose almost no DNA methylation in healthy cell types, but lose significant DNA methylation in many cancer types. This finding suggests that loss of DNA methylation at slow-loss CpGs could underlie some cancer-specific transcriptional deregulation that has been linked to DNA hypomethylation, including the derepression of cancer antigens and transposable elements.