Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration

Abstract

Mitotic inheritance of the DNA methylome is a challenging task for the maintenance of cell identity. Whether DNA methylation pattern in different genomic contexts can all be faithfully maintained is an open question. A replication-coupled DNA methylation maintenance model was proposed decades ago, but some observations suggest that a replication-uncoupled maintenance mechanism exists. However, the capacity and the underlying molecular events of replication-uncoupled maintenance are unclear. By measuring maintenance kinetics at the single-molecule level and assessing mutant cells with perturbation of various mechanisms, we found that the kinetics of replication-coupled maintenance are governed by the UHRF1-Ligase 1 and PCNA-DNMT1 interactions, whereas nucleosome occupancy and the interaction between UHRF1 and methylated H3K9 specifically regulate replication-uncoupled maintenance. Surprisingly, replication-uncoupled maintenance is sufficiently robust to largely restore the methylome when replication-coupled maintenance is severely impaired. However, solo-WCGW sites and other CpG sites displaying aging-and cancer-associated hypomethylation exhibit low maintenance efficiency, suggesting that although quite robust, mitotic inheritance of methylation is imperfect and that this imperfection may contribute to selective hypomethylation during aging and tumorigenesis.

The histone and non-histone methyllysine reader activities of the UHRF1 tandem Tudor domain are dispensable for the propagation of aberrant DNA methylation patterning in cancer cells

“…A recent study suggested that disruption of LIG1K126 or mutation of the UHRF1 TTD perturbed only the "replication-coupled" (less than 20 min after thymidine release) maintenance of DNA methylation, but that this defect was repaired by the end of S-phase, resulting in no measurable effect on DNA methylation in bulk cell populations [49]. The implication is that methyllysine recognition by UHRF1 may provide a slight increase in efficiency for maintenance methylation.…”

The Role of microRNAs in Organismal and Skin Aging

“…Epigenetic regulation plays a critical role in controlling the expression of various genetic elements. For example, DNA methylation and histone modifications are responsible for X chromosome inactivation and the repression of repetitive elements [ 134 ], such as transposable elements, telomeres, and centromeric DNA [ 4 ]. In turn, condensed chromatin limits recombination and decreases the risk of mutation, therefore facilitating genomic stability.…”

Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes

“…Partially methylated domains (PMDs) in tumor cells are mainly composed of prairies(Xue et al, 2020) and PMD hypomethylation increases with age, which appears to track the accumulation of cell divisions(Zhou et al, 2018). Xuan Ming et al also found that solo-WCGW sites display aging- and cancer-associated hypomethylation, which exhibit low maintenance efficiency during cell cycle(Ming et al, 2020). For chromatin structural changes, we compared the segregation ratio in G1 stage to that in the late S ~ G2 stage, and found that forest and prairie tend to become more separated in the late S ~ G2 stage (the related figure can be found in Xue et al, 2020).…”