{"doi":"10.1101/2022.04.14.485664","title":"Cell division drives DNA methylation loss in late-replicating domains in primary human cells","abstract":"DNA methylation undergoes dramatic age-related changes, first described more than four decades ago 1–4 . Loss of DNA methylation at late-replicating regions of the genome attached to the nuclear lamina advances with age in normal tissues, and is further exacerbated in cancer 5–7 . We present here the first experimental evidence that this DNA hypomethylation is directly driven by proliferation-associated DNA replication. Loss of DNA methylation at low-density CpGs in A:T-rich, p artially m ethylated d omains (PMD solo-WCGWs), tracks cumulative population doublings in primary cell culture. Cell cycle deceleration resulted in a proportional decrease in the rate of DNA hypomethylation. Blocking DNA replication via Mitomycin C treatment halted methylation loss. Loss of methylation continued unabated after TERT immortalization until finally reaching a severely hypomethylated equilibrium. Ambient oxygen culture conditions increased the rate of methylation loss compared to low-oxygen conditions, suggesting that some methylation loss may occur during unscheduled, oxidative damage repair-associated DNA synthesis. Finally, we present and validate a model to estimate the relative cumulative replicative histories of human cells, which we call “RepliTali” ( Repli cation T imes A ccumulated in Li fetime).","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299142,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":853656,"name":"Paula A. Nolte","orcid":null,"position":1,"is_corresponding":false},{"id":14040,"name":"Hui Shen","orcid":"0000-0001-9767-4084","position":2,"is_corresponding":false},{"id":279356,"name":"Peter W. Laird","orcid":"0000-0001-9117-3641","position":3,"is_corresponding":false},{"id":853655,"name":"Jamie L. Endicott","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T00:31:40.528568Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}