{"doi":"10.1101/2025.09.16.676613","title":"EZH1-dependent H3K27me1 is an adaptive chromatin barrier that limits DNMT inhibitor response in colorectal cancer","abstract":"Abstract Abnormal DNA methylation patterning is a defining epigenetic hallmark of human cancer and is therapeutically targetable with DNA methyltransferase inhibitors (DNMTi’s). However, DNMTi-induced DNA hypomethylation promotes adaptive chromatin remodeling that limits molecular and therapeutic responses to these drugs. Here, we identify EZH1-dependent H3K27 mono-methylation (H3K27me1) as a previously unrecognized adaptive barrier to DNMTi response in colorectal cancer. While EZH2-selective inhibitors deplete H3K27me2 and H3K27me3, they preserve EZH1-dependent H3K27me1 at Polycomb-enriched genomic regions. In contrast, dual EZH1/2 inhibition eliminates all H3K27 methylation states and robustly synergizes with DNMTi to enhance transcriptional activation and growth suppression. Mechanistically, dual EZH1/2 inhibition induces a redistribution of p300/CBP-dependent H3K27 acetylation (H3K27ac), generating a therapy-associated bivalent chromatin state characterized by coexisting DNA methylation and H3K27ac. DNMT inhibition resolves this induced bivalency, enabling activation of tumor-suppressive transcriptional programs. At the same time, coordinated loss of H3K27me1 and gene-body DNA methylation, together with depletion of promoter-associated H3K27ac, suppresses MYC- and E2F-driven oncogenic transcription networks that define the cancer cell-intrinsic therapeutic response. Collectively, these findings establish EZH1-dependent H3K27me1 as a key mediator of adaptive epigenetic plasticity and provide mechanistic rationale for combining DNMT inhibitors with dual EZH1/2i inhibitors to reprogram chromatin and suppress oncogenic transcription in solid tumors. Highlights EZH1-dependent H3K27me1 sustains an adaptive barrier to DNMT inhibitor response in colorectal cancer. Dual EZH1/2 inhibition eliminates all H3K27 methylation states and remodels chromatin architecture. EZH inhibition induces a DNA methylation-H3K27ac bivalent chromatin state. DNMT and EZH1/2 co-inhibition reprograms enhancers and promoters to activate tumor-suppressive pathways. Combination therapy suppresses MYC/E2F-driven oncogenic transcription, defining its cancer cell-intrinsic therapeutic efficacy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":575348,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":619275,"name":"Ashley K. Wiseman","orcid":"0009-0007-9760-0916","position":1,"is_corresponding":false},{"id":820875,"name":"Joel Hrit","orcid":"0000-0002-4497-956X","position":2,"is_corresponding":false},{"id":1028109,"name":"Yanqing Liu","orcid":"0000-0002-2342-3431","position":3,"is_corresponding":false},{"id":563067,"name":"Stephanie Stransky","orcid":"0000-0003-0844-2754","position":4,"is_corresponding":false},{"id":567005,"name":"Ying Cui","orcid":"0000-0002-4534-1904","position":5,"is_corresponding":false},{"id":741838,"name":"Xiangqian Kong","orcid":"0009-0006-1670-8929","position":6,"is_corresponding":false},{"id":644952,"name":"Michael J. Topper","orcid":"0000-0002-2778-4920","position":7,"is_corresponding":false},{"id":1841,"name":"Stephen B. Baylin","orcid":"0000-0003-3697-3798","position":8,"is_corresponding":false},{"id":247704,"name":"Simone Sidoli","orcid":"0000-0001-9073-6641","position":9,"is_corresponding":false},{"id":285624,"name":"Rochelle L. Tiedemann","orcid":"0009-0008-8408-9984","position":10,"is_corresponding":false},{"id":282215,"name":"Scott B. Rothbart","orcid":"0000-0003-1631-5392","position":11,"is_corresponding":false},{"id":285623,"name":"Alison A. Chomiak","orcid":"0000-0002-5036-3390","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":"41000734","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":[]}