{"doi":"10.1016/j.omtn.2023.02.024","title":"Gene-repressing epigenetic reader EED unexpectedly enhances cyclinD1 gene activation","abstract":"Epigenetically switched, proliferative vascular smooth muscle cells (SMCs) form neointima, engendering stenotic diseases. Histone-3 lysine-27 trimethylation (H3K27me3) and acetylation (H3K27ac) marks are associated with gene repression and activation, respectively. The polycomb protein embryonic ectoderm development (EED) reads H3K27me3 and also enhances its deposition, hence is a canonical gene repressor. However, herein we found an unexpected role for EED in activating the bona fide pro-proliferative gene Ccnd1 (cyclinD1). EED overexpression in SMCs increased Ccnd1 mRNA, seemingly contradicting its gene-repressing function. However, consistently, EED co-immunoprecipitated with gene-activating H3K27ac reader BRD4, and they co-occupied at both mitogen-activated Ccnd1 and mitogen-repressed P57 ( bona fide anti-proliferative gene), as indicated by chromatin immunoprecipitation qPCR. These results were abolished by an inhibitor of either the EED/H3K27me3 or BRD4/H3K27ac reader function. In accordance, elevating BRD4 increased H3K27me3. In vivo , while EED was upregulated in rat and human neointimal lesions, selective EED inhibition abated angioplasty-induced neointima and reduced cyclinD1 in rat carotid arteries. Thus, results uncover a previously unknown role for EED in Ccnd1 activation, likely via its cooperativity with BRD4 that enhances each other's reader function; i.e., activating pro-proliferative Ccnd1 while repressing anti-proliferative P57 . As such, this study confers mechanistic implications for the epigenetic intervention of neointimal pathology.","journal":"Molecular Therapy — Nucleic Acids","year":2023,"id":360258,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9483,"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":467358,"name":"Jing Li","orcid":"0000-0001-9593-6765","position":1,"is_corresponding":false},{"id":580468,"name":"Qingwei Wang","orcid":"0000-0002-2106-894X","position":2,"is_corresponding":false},{"id":366594,"name":"Go Urabe","orcid":"0000-0002-6536-0395","position":3,"is_corresponding":false},{"id":1070448,"name":"Runze Tang","orcid":"0000-0003-1127-6726","position":4,"is_corresponding":false},{"id":366593,"name":"Yitao Huang","orcid":"0000-0002-9005-6731","position":5,"is_corresponding":false},{"id":558981,"name":"José Verdezoto Mosquera","orcid":"0000-0002-2816-2250","position":6,"is_corresponding":false},{"id":366599,"name":"K. Craig Kent","orcid":"0000-0002-3684-6601","position":7,"is_corresponding":false},{"id":829258,"name":"Bowen Wang","orcid":"0000-0001-5794-2144","position":8,"is_corresponding":false},{"id":236712,"name":"Clint L. Miller","orcid":"0000-0003-4276-3607","position":9,"is_corresponding":false},{"id":366600,"name":"Lian‐Wang Guo","orcid":"0000-0002-6947-1578","position":10,"is_corresponding":false},{"id":366595,"name":"Mengxue Zhang","orcid":"0000-0002-0797-0881","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:14:01.896928Z","pmid":"36923952","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":[]}