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A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus [4C-seq]

ABSTRACT: Dysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternal Gtl2 lncRNA by precluding de novo DNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entire Dlk1-Dio3 locus. Although the targeted repression of either IG-DMR or Gtl2 promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control of Dlk1-Dio3 imprinting by allele-specific restriction of the active DNA (de)methylation machinery.

ORGANISM(S): Mus musculus Mus musculus molossinus

PROVIDER: GSE148315 | GEO | 2021/09/14

REPOSITORIES: GEO

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Imprinted gene expression at the Dlk1-Dio3 cluster is controlled by both maternal and paternal IG-DMRs in a tissue-specific fashion.

Project description:Imprinting at the Dlk1-Dio3 cluster is controlled by the IG-DMR, an imprinting control region differentially methylated between maternal and paternal chromosomes. The maternal IG-DMR is essential for imprinting control, functioning as a cis enhancer element. Meanwhile, DNA methylation at the paternal IG-DMR is thought to prevent enhancer activity. To explore whether suppression of enhancer activity at the methylated IG-DMR requires the transcriptional repressor TRIM28, we analyzed Trim28chatwo embryos and performed epistatic experiments with IG-DMR deletion mutants. We found that while TRIM28 regulates the enhancer properties of the paternal IG-DMR, it also controls imprinting through other mechanisms. Additionally, we found that the paternal IG-DMR, previously deemed dispensable for imprinting, is required in certain tissues, demonstrating that imprinting is regulated in a tissue-specific manner. Using ChRO-seq to analyze nascent transcription, we show that different tissues have a distinctive regulatory landscape at the Dlk1-Dio3 cluster, providing insight into potential mechanisms of tissue-specific imprinting control. ChRO-seq identified 30 novel transcribed regulatory elements, including a candidate regulatory region that depends on the paternal IG-DMR. Together, our findings challenge the model that Dlk1-Dio3 imprinting is regulated through a single mechanism and demonstrate that different tissues use distinct strategies for imprinting control.

2019-02-28 | GSE119882 | GEO

Loss of imprinting at the CTCF binding sites in the DLK1-DIO3 domain reactivates microRNA expression in acute promyelocytic leukaemia

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2014-02-13 | E-GEOD-42543 | biostudies-arrayexpress

Loss of imprinting at the CTCF binding sites in the DLK1-DIO3 domain reactivates microRNA expression in acute promyelocytic leukaemia

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Meg3 non-coding RNA expression controls imprinting by preventing transcriptional up-regulation in cis

Project description:Although many long non-coding RNAs (lncRNAs) are controlled by genomic imprinting, their roles often remain unknown. The Dlk1-Dio3 imprinted domain expresses the lncRNA Meg3 (also called Gtl2) and multiple microRNAs and snoRNAs from the maternal chromosome. This locus constitutes an epigenetic model for pluripotency and development, particularly for neurogenesis. The domain’s Dlk1 (Delta-like-1) gene encodes a ligand that inhibits Notch1 signalling and regulates diverse developmental processes. Using a hybrid embryonic stem (ES) cell system, we find that Dlk1 becomes imprinted during neural differentiation and that this involves chromatin activation and transcriptional up-regulation on the paternal chromosome. On the maternal chromosome, the Dlk1 gene remains poised. This allelic protection against gene activation is controlled in cis by Meg3 expression and also involves the H3-lysine-27 methyltransferase Ezh2. Maternal Meg3 expression additionally protects against de novo DNA methylation at its promoter. Concordantly, we find that the lncRNA Meg3 is nuclear, accumulates onto the imprinted locus and overlaps in cis with Dlk1 in embryonic cells. Our data evoke an imprinting model in which a mono-allelic lncRNA prevents chromatin and gene activation in cis during development.

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Gene expression changes in the intestinal crypts of mice with loss of imprinting

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2010-05-25 | E-GEOD-8583 | biostudies-arrayexpress

A permissive chromatin state regulated by ZFP281-AFF3 in controlling the imprinted Meg3 polycistron

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2016-12-08 | GSE77115 | GEO

Maternal RNA transcription in Dlk1-Dio3 domain is critical for proper development of the mouse placental vasculature

Project description:Maternal RNA transcription plays important roles in maintaining vasculature in mouse placental development associated with regulating gene expression, imprinting status and DNA methylation in the Dlk1-Dio3 imprinted domain.

2024-02-20 | GSE255900 | GEO

The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Project description:Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated patient-derived induced pluripotent stem cells (iPSCs) harboring distinct deletions in the affected region on chromosome 15. Studying PWS-iPSCs and human parthenogenetic iPSCs unexpectedly revealed substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we identified IPW, a long noncoding RNA in the critical region of the PWS locus, as a regulator of the DLK1-DIO3 region, as its over-expression in PWS and parthenogenetic iPSCs results in downregulation of the MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications, rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region. Gene expression analysis was performed on a total of 4 human cell lines, including 3 Prader-Willi Syndrome indcued pluripotent stem cell lines - derived from 3 affected individuals and one of their parental fibroblast cell line.

2014-04-03 | E-GEOD-56136 | biostudies-arrayexpress

The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

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The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation

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