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bioRxiv · 10.1101/2022.08.16.504069

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

Bar, D.·Fishman, L.·Zheng, Y.·Unterman, I.·Schlesinger, D.·Eden, A.·Lin, D.-C.·Berman, B. P.
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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.

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Bar, D., Fishman, L., Zheng, Y., Unterman, I., Schlesinger, D., Eden, A., Lin, D.-C., Berman, B. P.. 2022-08-17. A local sequence signature defines a subset of heterochromatin-associated CpGs with minimal loss of methylation in healthy tissues but extensive loss in cancer. https://doi.org/10.1101/2022.08.16.504069

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