4.7 Article

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

Journal

DEVELOPMENTAL CELL
Volume 56, Issue 22, Pages 3052-+

Publisher

CELL PRESS
DOI: 10.1016/j.devcel.2021.10.004

Keywords

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Funding

  1. National Health Institutes
  2. National Cancer Institute (NCI) [T32 CA203702]
  3. Lady TATA Memorial Fund
  4. Lymphoma Research Foundation
  5. NCI [P01CA229086, R01CA252239]
  6. NICHD [T32HD060600, F30HD097926]
  7. Medical Scientist Training Program grant from the NIGMS [T32GM007739]
  8. NIH [R01GM121994, DP2DA043813, R01GM138635]
  9. Tri-Institutional Stem Cell Initiative by the Starr Foundation (Tri-SCI)
  10. Edward Mallinck-rodt Jr. Foundation
  11. Tri-SCI

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The study reveals the importance of the IG-DMR in maintaining imprinting, which consists of a paternally methylated CpG island and a maternally unmethylated enhancer that counteracts DNA methyltransferases to ensure Gtl2 lncRNA expression. Genetic or epigenetic editing of these elements leads to distinct LOI phenotypes with characteristic alterations in allele-specific gene expression, DNA methylation, and 3D chromatin topology. The stability of LOI phenotypes depends on the IG-DMR, establishing it as a bipartite control element that maintains imprinting by allele-specific restriction of the DNA (de)methylation machinery.
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.

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