1. A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus
- Author
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Aristotelis Tsirigos, Hynek Wichterle, Effie Apostolou, Boaz E. Aronson, Emily Swanzey, Abhishek Sinha, Rachel A. Glenn, Annabel Azziz, Veevek Shah, Laurianne Scourzic, Jiexi Li, Meelad M. Dawlaty, Matthias Stadtfeld, Inbal Caspi, Thomas Vierbuchen, Bobbie Pelham-Webb, Andreas Kloetgen, Alexander Polyzos, and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
- Subjects
Methyltransferase ,Biology ,Iodide Peroxidase ,General Biochemistry, Genetics and Molecular Biology ,Chromosomes ,Article ,Mice ,Genomic Imprinting ,bipartite element ,Neoplasms ,Epigenome editing ,Animals ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Alleles ,Genetics ,DNA methylation ,IG-DMR ,Calcium-Binding Proteins ,Membrane Proteins ,Cell Biology ,Methylation ,DNA Methylation ,Dlk1-Dio3 ,Chromatin ,genomic imprinting ,Tet enzymes ,CpG site ,epigenome editing ,Intercellular Signaling Peptides and Proteins ,Dnmt3 ,RNA, Long Noncoding ,enhancer ,pluripotent stem cells ,Genomic imprinting ,Developmental Biology - Abstract
Summary 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.
- Published
- 2021