DNA methylation loss in late-replicating domains is linked to mitotic cell division
Zhou W, Dinh HQ, Ramjan Z, Weisenberger DJ, Nicolet CM, Shen H, Laird PW, Berman BP. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat Genet. 2018 Apr;50(4):591-602. doi: 10.1038/s41588-018-0073-4. Epub 2018 Apr 2. PMID: 29610480; PMCID: PMC5893360.
This study identifies four influencers of DNA methylation levels in human and mouse genomes.
Local sequence context of the CpG dinucleotide
CpG density and the WCGW sequence context strongly influence the rate of DNA methylation loss at individual CpGs within the Partially Methylated Domains (PMDs). Their influences are constant between cell types and species. Solo-WCGW CpGs are prone to hypomethylation, possibly because DNMT1 has increased efficiency when there are multiple CpG sites close together.
Timing of DNA replication
Replication timing is a determinant of methylation levels at H3K36me3 negative CpGs like Solo-WCGW CpGs. Replication late in the S phase does not give the cell enough time to remethylate the daughter strands. Methylation during mitosis can be slow and may not fully be completed until the S-G2 checkpoint.
H3K36me3 histone mark
The presence of H3K36me3 can override the methylation loss associated with late-replication. H3K36me3 helps to maintain DNA methylation at marked CpGs by the recruitment of DNMT3B to the trimethylated nucleosomes. In carcinomas with NSD1 mutations and loss of H3K36me2 and H3K36me3, there is a loss of DNA methylation in areas of typically high methylation.
Accumulated number of cell divisions
PMD hypomethylation can accumulate despite DNA methylation maintenance machinery - genes associated with cell division and proliferation are also associated with PMD hypomethylation. The cumulative cell divisions can be a driver of PMD hypomethylation.