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dc.contributor.authorAronson, Boaz E
dc.contributor.authorScourzic, Laurianne
dc.contributor.authorShah, Veevek
dc.contributor.authorSwanzey, Emily
dc.contributor.authorKloetgen, Andreas
dc.contributor.authorPolyzos, Alexander
dc.contributor.authorSinha, Abhishek
dc.contributor.authorAzziz, Annabel
dc.contributor.authorCaspi, Inbal
dc.contributor.authorLi, Jiexi
dc.contributor.authorPelham-Webb, Bobbie
dc.contributor.authorGlenn, Rachel A
dc.contributor.authorVierbuchen, Thomas
dc.contributor.authorWichterle, Hynek
dc.contributor.authorTsirigos, Aristotelis
dc.contributor.authorDawlaty, Meelad M
dc.contributor.authorStadtfeld, Matthias
dc.contributor.authorApostolou, Effie
dc.date.accessioned2021-12-07T10:22:28Z
dc.date.available2021-12-07T10:22:28Z
dc.date.issued2021-10-27
dc.identifier.citationjDev Cell. 2021 Nov 22;56(22):3052-3065.e5. doi: 10.1016/j.devcel.2021.10.004. Epub 2021 Oct 27.en_US
dc.identifier.pmid34710357
dc.identifier.doi10.1016/j.devcel.2021.10.004
dc.identifier.urihttp://hdl.handle.net/10033/623113
dc.description.abstractLoss 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.en_US
dc.language.isoenen_US
dc.publisherElsevier (Cell Press)en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectDNA methylationen_US
dc.subjectDlk1-Dio3en_US
dc.subjectDnmt3en_US
dc.subjectIG-DMRen_US
dc.subjectTet enzymesen_US
dc.subjectbipartite elementen_US
dc.subjectenhanceren_US
dc.subjectepigenome editingen_US
dc.subjectgenomic imprintingen_US
dc.subjectpluripotent stem cellsen_US
dc.titleA bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus.en_US
dc.typeArticleen_US
dc.identifier.eissn1878-1551
dc.contributor.departmentBRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.en_US
dc.identifier.journalDevelopmental cellen_US
dc.source.volume56
dc.source.issue22
dc.source.beginpage3052
dc.source.endpage3065.e5
refterms.dateFOA2021-12-07T10:22:29Z
dc.source.journaltitleDevelopmental cell
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International