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Characterization of universal features of partially methylated domains across tissues and species.

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Qu, Jianghan 
Ji, Xiaojing 
Wagenblast, Elvin 
Knott, Simon RV 


BACKGROUND: Partially methylated domains (PMDs) are a hallmark of epigenomes in reproducible and specific biological contexts, including cancer cells, the placenta, and cultured cell lines. 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. RESULTS: 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. 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. 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. CONCLUSIONS: 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.



Cancer, DNA methylation, Hidden Markov models, Partially methylated domains, Animals, Cell Line, Tumor, Cells, Cultured, DNA Methylation, Epigenome, Female, Gene Expression Regulation, Neoplastic, Humans, Lung, Mammary Glands, Human, Mice, Mice, Inbred C57BL, Organ Specificity, Placenta, Pregnancy, Species Specificity

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Epigenetics Chromatin

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Springer Science and Business Media LLC