![]() PMDs can be reliably produced by immortalizing human B-lymphocytes with Epstein–Barr virus (EBV ), and can be erased by inducing pluripotency. PMDs in a breast cancer cell line largely overlap genomic regions occupied by histone modifications H3K9me3 or H3K27me3, suggesting a link between PMDs and repressive chromatin that has been further validated by association of PMDs with repressive chromatin states identified by ChromHMM. CpG island methylation inside PMDs is pronounced in many cancers and subtle but significant in placenta, though it is unknown whether this methylation occurs via the same underlying mechanisms as in cancer methylomes. Boundaries of PMDs are enriched for genomic regulatory features including promoters and insulators, often containing or defined by CTCF sites. Despite this general trend, their locations show some degree of cell-type specificity. They generally reside in gene-sparse genomic locations and coincide with lamina-associated domains and late-replicating regions. Īn increasing number of studies have uncovered several genomic and epigenomic features associated with PMDs. In addition to cancers and cultured cells, PMDs have been identified in the placenta at multiple developmental stages and in several species. ![]() When they exist, PMDs can cover as much as half the genome, with many contiguous domains larger than 1 megabase. Further WGBS studies have established PMDs as a universal feature in methylomes of cancers and cultured cells. Subsequent studies found these broad domains of reduced methylation to be prevalent in cancer methylomes, and we can now attribute the aforementioned global hypomethylation observed in early cancer studies to this phenomenon. ![]() One of the most striking features to emerge from the first application of this technique in mammals were partially methylated domains (PMDs), which were observed in a human lung fibroblast cell line but not in embryonic stem cells. The development of modern whole-genome bisulfite sequencing (WGBS) allowed for a high-resolution and full-genome view of DNA methylation. Early studies of DNA methylation in cancer discovered a globally reduced level of methylation, compared to healthy tissue analogues. ![]() Our improved method makes low sequencing depth, population-level studies of PMD variation possible and our results further refine the model of PMD formation as one where sequence context and regional epigenomic features both play a role in gradual genome-wide hypomethylation.ĭNA methylation is associated with a variety of gene regulatory functions in mammals, working in concert with histone marks to stably repress transcription. We also explored the discordant PMD state of orthologous genes between human and mouse, and observed a directional association of PMD state with gene expression and local gene density. Applying our method to 267 methylomes from 7 species, we corroborated recent results regarding the general association between replication timing and PMD state, and report identification of several reproducibly “escapee” genes within late-replicating domains that escape the reduced expression and hypomethylation of their immediate genomic neighborhood. In this study, we outline a set of axioms that take a step towards a functional definition for PMDs, describe an improved method for comparable PMD detection across samples with substantially differing sequencing depths, and refine the decision criteria for whether a sample contains PMDs using a data-driven approach. Existing methods for deciding whether PMDs exist in a sample, as well as their identification, are few, often tailored to specific biological questions, and require high coverage samples for accurate identification. Partially methylated domains (PMDs) are a hallmark of epigenomes in reproducible and specific biological contexts, including cancer cells, the placenta, and cultured cell lines.
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