{"doi":"10.7554/elife.85595","title":"Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome","abstract":"The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O -GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O -GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O -GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O -GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O -GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.","journal":"eLife","year":2023,"id":337459,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":457337,"name":"Amy Leung","orcid":"0000-0002-5175-430X","position":1,"is_corresponding":false},{"id":576954,"name":"Kevin R Costello","orcid":"0000-0001-6104-0776","position":2,"is_corresponding":false},{"id":281426,"name":"Parijat Senapati","orcid":"0000-0002-7324-1230","position":3,"is_corresponding":false},{"id":597183,"name":"Hiroyuki Kato","orcid":"0000-0002-5748-3221","position":4,"is_corresponding":false},{"id":986478,"name":"Roger E. Moore","orcid":"0000-0002-8907-2144","position":5,"is_corresponding":false},{"id":999470,"name":"Michael Lee","orcid":"0000-0002-3676-3435","position":6,"is_corresponding":false},{"id":1069280,"name":"Dimitri Lin","orcid":null,"position":7,"is_corresponding":false},{"id":303740,"name":"Xiaofang Tang","orcid":"0009-0002-2972-8778","position":8,"is_corresponding":false},{"id":339633,"name":"Patrick Pirrotte","orcid":"0000-0003-1360-6039","position":9,"is_corresponding":false},{"id":297552,"name":"Zhen Chen","orcid":"0000-0002-3291-1090","position":10,"is_corresponding":false},{"id":281431,"name":"Dustin E. Schones","orcid":"0000-0001-7692-8583","position":11,"is_corresponding":false},{"id":576955,"name":"Heon Shin","orcid":"0000-0001-5480-8492","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T01:10:26.690308Z","pmid":"37470704","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":[]}