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

Document Type

Article

Publication Date

11-22-2021

Publication Title

Developmental cell

Keywords

Alleles, Animals, Calcium-Binding Proteins, Chromosomes, DNA Methylation, Genomic Imprinting, Intercellular Signaling Peptides and Proteins, Iodide Peroxidase, Mice, Promoter Regions, Genetic, RNA, Long Noncoding

JAX Location

JMG

Volume

56

Issue

22

First Page

3052

Last Page

3065

ISSN

1878-1551

PMID

34710357

DOI

https://doi.org/10.1016/j.devcel.2021.10.004

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.

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