Characterization of universal features of partially methylated domains across tissues and species
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Epigenetics & Chromatin Open Access
RESEARCH
Characterization of universal features of partially methylated domains across tissues and species Benjamin E. Decato1* , Jianghan Qu1, Xiaojing Ji1, Elvin Wagenblast2,5,6, Simon R. V. Knott2,3,4, Gregory J. Hannon2,3,7 and Andrew D. Smith1*
Abstract 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. Keywords: Partially methylated domains, DNA methylation, Cancer, Hidden Markov models Background DNA methylation is associated with a variety of gene regulatory functions in mammals, working in concert with histone marks to stably repress transcription. Early studies of DNA methylation in cancer discovered a globally reduced level of methylation, compared to healthy tissue analogues [1, 2]. The development of modern whole-genome bisulfite sequencing (WGBS) allowed for *Correspondence: [email protected]; [email protected] 1 Quantitative and Computational Biology Section, University of Southern California, Childs Way, Los Angeles, California, USA Full list of author information is available at the end of the article
a high-resolution and full-genome view of DNA methylation. 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 [3]. Subsequent studies found these broad domains of reduced methylation to be prevalent in cancer methylomes [4, 5], and we can now attribute the aforementioned global hypomethylation o
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