Abstract
BackgroundPartially methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level. They cover gene-poor and transcriptionally inactive regions and tend to be heterochromatic. We present a comprehensive comparative analysis of partially methylated domains in human and mouse cells, to identify structural and functional features associated with them.ResultsPartially methylated domains are present in up to 75% of the genome in human and mouse cells irrespective of their tissue or cell origin. Each cell type has a distinct set of partially methylated domains, and genes expressed in such domains show a strong cell type effect. The methylation level varies between cell types with a more pronounced effect in differentiating and replicating cells. The lowest level of methylation is observed in highly proliferating and immortal cancer cell lines. A decrease of DNA methylation within partially methylated domains tends to be linked to an increase in heterochromatic histone marks and a decrease of gene expression. Characteristic combinations of heterochromatic signatures in partially methylated domains are linked to domains of early and middle S-phase and late S-G2 phases of DNA replication.ConclusionsPartially methylated domains are prominent signatures of long-range epigenomic organization. Integrative analysis identifies them as important general, lineage- and cell type-specific topological features. Changes in partially methylated domains are hallmarks of cell differentiation, with decreased methylation levels and increased heterochromatic marks being linked to enhanced cell proliferation. In combination with broad histone marks, partially methylated domains demarcate distinct domains of late DNA replication.
Highlights
Methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level
Genomic region enrichment analysis for such differentially methylated region (DMR) using GREAT [36] provides cell differentiation and development relevant as major terms (Additional file 2: Figure S20). These findings demonstrate the advantage of stratifying DMRs according to increasing and decreasing of DNA methylation in highly methylated domains (HMDs) and partially methylated domains (PMDs), affording more insight into the biological role of the genes associated with these DMRs
As this study only focused on DNA methylation, it remains an open question if B compartments are established prior to a heterochromatic domain formation which we see as one feature of cell-type-specific PMDs
Summary
Methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level. They cover gene-poor and transcriptionally inactive regions and tend to be heterochromatic. Several studies have since reported PMDs in various cell types: medulloblastoma [6], adipocyte tissue [7], SH-SY5Y neuronal cells [8], and human cancers [5, 9,10,11]. PMDs in cancer cells are Salhab et al Genome Biology (2018) 19:150 linked to late replication and nuclear lamina-associated regions [10]. The first non-cancer primary human tissue type with PMDs has been reported in placenta [12]
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