ArticleDevelopmental cell2021
A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus.
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Article in Developmental cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 25 citations in OpenAlex.
- Transcriptomic and miRNA-Target Pathway Analysis of the DLK1-DIO3 Imprinted microRNA Cluster in Chronic Lymphocytic Leukemia.Diseases (Basel, Switzerland) · 2026Article
- Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming.Nature communications · 2026Article
- Regulatory mechanisms of maternal imprinting at the murine Dlk1-Dio3 domain.Nature communications · 2026Article
- Allele-specific CRISPR perturbation of the imprinted Dlk1-Dio3 domain reveals regulation of BMP-NOTCH-VEGF signaling in embryonic organogenesis.Cell death and differentiation · 2026Article
- DNA methylation and lncRNA control asynchronous DNA replication at specific imprinted gene domains.Nature communications · 2026Article
- The superpowers of imprinting control regions.Genome research · 2026Review
- Challenges and emerging strategies for genome-wide evaluation of loss of imprinting in cancer.British journal of biomedical science · 2026Review
- TET3 protects theiScience · 2025Article
- Enhanced Notch dependent gliogenesis and delayed physiological maturation underlie neurodevelopmental defects in Lowe syndrome.EMBO molecular medicine · 2025Article
- A molecular circuit regulates fate plasticity in emerging and adult AT2 cells.Nature communications · 2025Article
- Identification of maternal allele sequences of IG-DMR that are essential for neonatal viability.PloS one · 2025Article
- Silencing of maternally expressed RNAs in Dlk1-Dio3 domain causes fatal vascular injury in the fetal liver.Cellular and molecular life sciences : CMLS · 2024Article
- Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia.Nature communications · 2024Article
- The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation.Nucleic acids research · 2024Article
- Maternal RNA transcription in Dlk1-Dio3 domain is critical for proper development of the mouse placental vasculature.Communications biology · 2024Article
- The role of imprinting genes' loss of imprints in cancers and their clinical implications.Frontiers in oncology · 2024Review
- Review
- Protocol for DNA Methylation Editing of Imprinted Loci and Assessment of the Effects.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Epigenetic mechanism of Gtl2-miRNAs causes the primitive sheep characteristics found in purebred Merino sheep.Cell & bioscience · 2023Article
- Embryonic transcription and epigenetics: root of the evil.Human cell · 2023Article
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Authors and funding
18 authors at 2 institutions in 1 country.
Boaz E AronsonSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA.
Laurianne ScourzicSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA.
Veevek ShahSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA.
Emily SwanzeySanford I Weill Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jackson Laboratory, Bar Harbor, ME, USA.
Andreas KloetgenDepartment of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Alexander PolyzosSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA.
Abhishek SinhaDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Annabel AzzizWeill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
Inbal CaspiDevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jiexi LiSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA.
Bobbie Pelham-WebbWeill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD program, New York, NY, USA.
Rachel A GlennWeill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Stem Cell Biology and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Thomas VierbuchenDevelopmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Stem Cell Biology and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Hynek WichterleDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neurology, Neuroscience and Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, Center for Motor Neuron Biology and Disease and Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA.
Aristotelis TsirigosDepartment of Pathology, New York University School of Medicine, New York, NY 10016, USA; Institute for Computational Medicine and Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY 10016, USA.
Meelad M DawlatyRuth L and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Bronx, NY 10461, USA; Department of Genetics, Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Matthias StadtfeldSanford I Weill Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: mas4011@med.cornell.edu.
Effie ApostolouSanford I Weill Department of Medicine, Division of Hematology/Oncology, Sandra and Edward Meyer Cancer Center, New York, NY 10021, USA. Electronic address: efa2001@med.cornell.edu.
Weill Cornell Medicine · USCornell University · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MWeill Cornell/Rockefeller/Sloan-Kettering MST ProgramT32GM007739 · NIGMS · WEILL MEDICAL COLL OF CORNELL UNIV · PI HSU, KATHARINE C · 1985 to 2023
$51.1MThe impact of changes in chromatin architecture on cancer phenotypes and tumor progressionP01CA229086 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ADRIANA HEGUY · 2019 to 2026
$17.0MSUPPORT FOR THE ROSE F KENNEDY IDDRC P50P50HD105352 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI SOPHIE MOLHOLM, Steven Upshaw Walkley · 2021 to 2026
$7.0MTargeting Epigenetic Heterogeneity in Pediatric T cell leukemia: Epi-Clones as Drivers of ChemoresistanceR01CA252239 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Aristotelis Tsirigos · 2021 to 2026
$3.7MTraining Program in Developmental BiologyT32HD060600 · NICHD · WEILL MEDICAL COLL OF CORNELL UNIV · PI BAO, ZHIRONG, STUHLMANN, HEIDI · 2010 to 2024
$3.5MDefining the role of chromatin architecture in cell fate inheritanceDP2DA043813 · NIDA · WEILL MEDICAL COLL OF CORNELL UNIV · PI APOSTOLOU, EFFIE · 2016 to 2016
$2.5MOrganizational principles and functional role of 3D enhancer hubs in cell fate decisionsR01GM138635 · NIGMS · WEILL MEDICAL COLL OF CORNELL UNIV · PI APOSTOLOU, EFFIE · 2020 to 2023
$1.9MMaintenance of epigenetic integrity during nuclear reprogrammingR01GM111852 · NIGMS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI STADTFELD, MATTHIAS · 2014 to 2018
$1.6MStructural basis of the Ragulator-Rag GTPase complex as a platform for mTOR activation on the lysosomal surfaceR01GM121994 · NIGMS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI WANG, DANENG · 2017 to 2020
$1.5MMolecular and Translational Oncology ResearchT32CA203702 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI BLENIS, JOHN, GIANNAKAKOU, PARASKEVI · 2017 to 2021
$1.4MThe Role of Mitotic Bookmarking in the Molecular Resetting of the Pluripotent Stem Cell IdentityF30HD097926 · NICHD · WEILL MEDICAL COLL OF CORNELL UNIV · PI PELHAM-WEBB, BOBBIE · 2019 to 2020
$94kNCI NIH HHS P01 CA229086NCI NIH HHS P30 CA008748NCI NIH HHS R01 CA252239NCI NIH HHS T32 CA203702NICHD NIH HHS F30 HD097926NICHD NIH HHS P50 HD105352NICHD NIH HHS T32 HD060600NIDA NIH HHS DP2 DA043813NIGMS NIH HHS R01 GM111852NIGMS NIH HHS R01 GM121994NIGMS NIH HHS R01 GM138635NIGMS NIH HHS T32 GM007739
Abstract
Loss of imprinting (LOI) results in severe developmental defects, but the mechanisms preventing LOI remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) in pluripotent stem cells. We demonstrate that the IG-DMR consists of two antagonistic elements: a paternally methylated CpG island that prevents recruitment of TET dioxygenases and a maternally unmethylated non-canonical enhancer that ensures expression of the Gtl2 lncRNA by counteracting de novo DNA methyltransferases. Genetic or epigenetic editing of these elements leads to distinct LOI phenotypes with characteristic alternations of allele-specific gene expression, DNA methylation, and 3D chromatin topology. Although repression of the Gtl2 promoter results in dysregulated imprinting, the stability of LOI phenotypes depends on the IG-DMR, suggesting a functional hierarchy. These findings establish the IG-DMR as a bipartite control element that maintains imprinting by allele-specific restriction of the DNA (de)methylation machinery.
Indexed as
AllelesAnimalsCalcium-Binding ProteinsChromosomesDNA MethylationGenomic ImprintingIntercellular Signaling Peptides and ProteinsIodide PeroxidaseMicePromoter Regions, GeneticRNA, Long NoncodingCalcium-Binding ProteinsDlk1 protein, mouseIntercellular Signaling Peptides and ProteinsIodide Peroxidaseiodothyronine deiodinase type IIIRNA, Long Noncodingbipartite elementDlk1-Dio3DNA methylationDnmt3enhancerepigenome editinggenomic imprintingIG-DMRpluripotent stem cellsTet enzymes
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