{"doi":"10.1016/j.molcel.2025.08.025","title":"Requirements for establishment and epigenetic stability of mammalian heterochromatin","abstract":"Heterochromatic domains of DNA account for a large fraction of mammalian genomes and play critical roles in silencing transposons and genes, but the mechanisms that establish and maintain these domains are not fully understood. Here, we use a CRISPR-based genetic screen to investigate the requirements for establishment and maintenance of histone H3 lysine 9 trimethylation (H3K9me3) heterochromatin. In mouse embryonic stem cells (mESCs), we show that transiently induced H3K9me3 heterochromatin is inherited for a limited number of cell divisions, independently of sequence-dependent recruitment, but becomes stable upon differentiation, concomitant with downregulation of enzymes erasing H3K9me and DNA methylation. In addition, ordered and non-redundant activities of multiple H3K9 and DNA methyltransferases, together with histone deacetylases, chromatin remodeling complexes, and RNA processing factors, are required for heterochromatin maintenance. Our findings suggest that a newly acquired H3K9me3 domain can be maintained like an imprint but requires reinforcement by DNA methylation and other pathways.","journal":"Molecular Cell","year":2025,"id":514927,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"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":1378359,"name":"Harleen Saini","orcid":"0000-0001-6954-4098","position":1,"is_corresponding":false},{"id":696553,"name":"Juntao Yu","orcid":"0000-0003-3282-2781","position":2,"is_corresponding":false},{"id":828659,"name":"Wenzhi Feng","orcid":"0000-0002-5597-9530","position":3,"is_corresponding":false},{"id":989574,"name":"Carlos A. Pinzón-Arteaga","orcid":"0000-0002-4906-6751","position":4,"is_corresponding":false},{"id":353969,"name":"Danesh Moazed","orcid":"0000-0003-0321-6221","position":5,"is_corresponding":false},{"id":1378974,"name":"Antonis Tatarakis","orcid":null,"position":0,"is_corresponding":true}],"reference_count":116,"raw_metadata":null,"created_at":"2026-07-19T02:48:34.431522Z","pmid":"40972525","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":[]}