DNA methylation loss in late-replicating domains is linked to mitotic cell division

Abstract

DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed Partially Methylated Domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using Whole-Genome Bisulfite Sequencing (WGBS), and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (“Solo-WCGWs”) revealed previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell-cycle gene expression, consistent with its reflection of mitotic history, and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.

Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis

“…Due to the domain segregation and resulted different accessibility of forests and prairies, this hypomethylation is more likely to occur in the latter domains, enlarging the methylation difference between forests and prairies. Such a mechanism is also consistent with previous findings of hypomethylation in aging cells, and the extent of hypomethylation being proportional to the replication timing of the regions and the cell division rate of a tissue (24,48). In turn, the large methylation difference is expected to lead to a higher degree of segregation between forests and prairies.…”

“…Over ten thousands of publications reported DNA methylation changes as cancer biomarkers (22), but few have been applied to clinical diagnosis and treatment. While some studies provided examples to illustrate the regulation of between gene expression by DNA methylation, recently more evidences show that DNA methylation has little impact on gene expression but corresponds to chromosomal structural changes (23,24). However, the correlation between changes of DNA methylation and cancer samples.…”

Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation

“…65.4% of PMD base pairs were also identified as PMD in an independent WGBS dataset of NeuNsorted human neurons ( Figure S4C ). 40.361.0% of PMD bases per neuronal sample were identified as common PMD sequence, and 9.315.0% bases were additionally identified as PMD in at least one sample in a recent study profiling PMDs in multiple cell types and tissues 13 ( Figure S4D ). These data suggest that although the neuronal genome was overall highly methylated, a small but consistent portion displayed the characteristics of PMDs.…”

Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome

“…PMDs has recently been shown to constitute a biomarker of cellular aging 32 . To investigate whether the LAD-specific chromatin accessibility changes in HGPS cells are accompanied by alterations in DNA methylation, we performed DNA methylation profiling using Infinium MethylationEPIC BeadChips, which capture the methylation status of more than 850,000…”

“…In fact, they overlap to a large extent with partially methylated domains (PMDs) 30,31 , i.e., long stretches of DNA with reduced levels of DNA methylation. Interestingly, PMDs have also been shown to undergo hypomethylation as a consequence of mitotic cell division and cell aging 32 . Whether they also become differentially methylated in HGPS is still an open question.…”