{"doi":"10.1101/2020.05.22.103796","title":"A bipartite element with allele-specific functions safeguards DNA methylation imprints at the <i>Dlk1-Dio3</i> locus","abstract":"SUMMARY Dysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternal Gtl2 lncRNA by precluding de novo DNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entire Dlk1-Dio3 locus. Although the targeted repression of either IG-DMR or Gtl2 promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control of Dlk1-Dio3 imprinting by allele-specific restriction of the DNA (de)methylation machinery. HIGHLIGHTS The IG-DMR is a bipartite element with distinct allele-specific functions A non-canonical enhancer within the IG-DMR prevents DNA methyltransferase activity Targeted epigenome editing allows induction of specific imprinting phenotypes CRISPRi reveals a functional hierarchy between DMRs that dictates imprint stability","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129723,"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":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":581374,"name":"Laurianne Scourzic","orcid":"0000-0003-2875-1642","position":1,"is_corresponding":false},{"id":581375,"name":"Varsha Shah","orcid":"0000-0001-8131-9256","position":2,"is_corresponding":false},{"id":455286,"name":"Emily Swanzey","orcid":"0000-0003-2581-6498","position":3,"is_corresponding":false},{"id":228657,"name":"Andreas Kloetgen","orcid":"0000-0003-0991-4442","position":4,"is_corresponding":false},{"id":455284,"name":"Alexander Polyzos","orcid":"0000-0002-2509-9698","position":5,"is_corresponding":false},{"id":109949,"name":"Anupam Sinha","orcid":"0000-0002-2318-3511","position":6,"is_corresponding":false},{"id":581974,"name":"Annabel Azziz","orcid":null,"position":7,"is_corresponding":false},{"id":581376,"name":"Inbal Caspi","orcid":"0000-0003-1852-2643","position":8,"is_corresponding":false},{"id":581377,"name":"Jian Li","orcid":"0000-0003-3320-7924","position":9,"is_corresponding":false},{"id":329478,"name":"Bobbie Pelham‐Webb","orcid":"0000-0003-0437-8206","position":10,"is_corresponding":false},{"id":581378,"name":"Hynek Wichterle","orcid":"0000-0002-7817-0080","position":11,"is_corresponding":false},{"id":69214,"name":"Aristotelis Tsirigos","orcid":"0000-0002-7512-8477","position":12,"is_corresponding":false},{"id":455292,"name":"Matthias Stadtfeld","orcid":"0000-0002-5852-9906","position":13,"is_corresponding":false},{"id":56471,"name":"Effie Apostolou","orcid":"0000-0002-8111-0863","position":14,"is_corresponding":false},{"id":581973,"name":"BE Aronson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:49.682497Z","pmid":null,"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":[]}