{"doi":"10.1016/j.molcel.2024.11.009","title":"DNA hypomethylation promotes UHRF1-and SUV39H1/H2-dependent crosstalk between H3K18ub and H3K9me3 to reinforce heterochromatin states","abstract":"Mono-ubiquitination of lysine 18 on histone H3 (H3K18ub), catalyzed by UHRF1, is a DNMT1 docking site that facilitates replication-coupled DNA methylation maintenance. Its functions beyond this are unknown. Here, we genomically map simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/H2-dependent H3K9me3 following DNMT1 inhibition. Mechanistically, transient accumulation of hemi-methylated DNA at CpG islands facilitates UHRF1 recruitment and E3 ligase activity toward H3K18. Notably, H3K18ub enhances SUV39H1/H2 methyltransferase activity and, in colon cancer cells, nucleates new H3K9me3 domains at CpG island promoters of DNA methylation-silenced tumor suppressor genes (TSGs). Disrupting UHRF1 enzyme activity prevents H3K9me3 accumulation while promoting PRC2-dependent H3K27me3 as a tertiary layer of gene repression in these regions. By contrast, disrupting H3K18ub-dependent SUV39H1/H2 activity enhances the transcriptional activating and antiproliferative effects of DNMT1 inhibition. Collectively, these findings reveal roles for UHRF1 and H3K18ub in regulating a hierarchy of repressive histone methylation signaling and rationalize a combination strategy for epigenetic cancer therapy. • DNA hypomethylation leads to UHRF1-dependent increases in H3K18ub and H3K9me3 • Hemi-methylated DNA accumulation promotes H3K18ub that enhances SUV39H1/H2 activity • Disrupting UHRF1 activity prevents H3K9me3 accumulation but promotes PRC2 activity • Targeting H3K18ub stimulation of SUV39H1/H2 enhances DNMT1 inhibitor efficacy Liu et al. report that DNMT1 inhibition causes transient accumulation of hemi-methylated DNA at CpG islands, which stimulates UHRF1-mediated H3K18ub. This enhances SUV39H1/H2 activity, nucleates new H3K9me3 domains, and impedes PRC2 activity at DNA-methylation-silenced TSG promoters. Targeting this previously unrecognized H3K18ub-H3K9me3 crosstalk offers new strategies to enhance DNMT1 inhibitor therapy.","journal":"Molecular Cell","year":2024,"id":421469,"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":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":820875,"name":"Joel Hrit","orcid":"0000-0002-4497-956X","position":1,"is_corresponding":false},{"id":285623,"name":"Alison A. Chomiak","orcid":"0000-0002-5036-3390","position":2,"is_corresponding":false},{"id":563067,"name":"Stephanie Stransky","orcid":"0000-0003-0844-2754","position":3,"is_corresponding":false},{"id":1213796,"name":"Jordan R. Hoffman","orcid":"0000-0001-6055-0678","position":4,"is_corresponding":false},{"id":285624,"name":"Rochelle L. Tiedemann","orcid":"0009-0008-8408-9984","position":5,"is_corresponding":false},{"id":619275,"name":"Ashley K. Wiseman","orcid":"0009-0007-9760-0916","position":6,"is_corresponding":false},{"id":1214268,"name":"Leena S Kariapper","orcid":null,"position":7,"is_corresponding":false},{"id":407308,"name":"Bradley M. Dickson","orcid":"0000-0002-4995-9111","position":8,"is_corresponding":false},{"id":1213797,"name":"Evan J. Worden","orcid":"0000-0003-0644-166X","position":9,"is_corresponding":false},{"id":269410,"name":"Christopher J. Fry","orcid":null,"position":10,"is_corresponding":false},{"id":247704,"name":"Simone Sidoli","orcid":"0000-0001-9073-6641","position":11,"is_corresponding":false},{"id":282215,"name":"Scott B. Rothbart","orcid":"0000-0003-1631-5392","position":12,"is_corresponding":false},{"id":1028109,"name":"Yanqing Liu","orcid":"0000-0002-2342-3431","position":0,"is_corresponding":true}],"reference_count":120,"raw_metadata":null,"created_at":"2026-07-19T01:57:36.298171Z","pmid":"39631394","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":[]}