A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus

Boaz E. Aronson, Laurianne Scourzic, Veevek Shah, Emily Swanzey, Andreas Kloetgen, Alexander Polyzos, Abhishek Sinha, Annabel Azziz, Inbal Caspi, Jiexi Li, Bobbie Pelham-Webb, Rachel A. Glenn, Thomas Vierbuchen, Hynek Wichterle, Aristotelis Tsirigos, Meelad M. Dawlaty, Matthias Stadtfeld, Effie Apostolou

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3052-3065.e5
JournalDevelopmental cell
Issue number22
StatePublished - Nov 22 2021


  • DNA methylation
  • Dlk1-Dio3
  • Dnmt3
  • IG-DMR
  • Tet enzymes
  • bipartite element
  • enhancer
  • epigenome editing
  • genomic imprinting
  • pluripotent stem cells

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology


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