Cell division drives DNA methylation loss in late-replicating domains in primary human cells
Endicott JL, Nolte PA, Shen H, Laird PW. Cell division drives DNA methylation loss in late-replicating domains in primary human cells. Nat Commun. 2022 Nov 8;13(1):6659. doi: 10.1038/s41467-022-34268-8. PMID: 36347867; PMCID: PMC9643452.
Zhou et al. showed that there is a loss of DNA methylation at certain regions of the genome that they suggested was caused by mitosis. This paper experimentally shows that this loss is driven by cellular division independent of time. Methylation loss is negatively correlated with population doubling in a cell culture. It occurs more at solo-WGCWs, lone CG dinucleotides within a 35-bp region flanked by A or T nucleotides, than at social WGCWs. The loss is greater at regions that replcate late than earlier replication regions, which they believe is indicative of poor maintenance methylation and possibly chromatin inaccessibility. Most domains with solo-WGCWs are gene-poor, but those with highly expressed genes had lower rates of methylation loss in a cell-type specific manner. Stopping DNA replication stops the methylation loss. Ambient oxygen concentrations for cell culture lead to increased rates of methylation loss.
Using the collected methylation data, they build a model using elastic net regression to predict relative mitotic history. It performed better than other existing methods that were trained on comparisons between different time points, unlike this model which is based on measured cell divisions. It is however, best suited to single cell type populations since it was trained on homogeneious primary cell culture.