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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56136 | GEO | 2014/04/03

SECONDARY ACCESSION(S): PRJNA242529

REPOSITORIES: GEO

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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

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

Project description: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.

2021-09-14 | GSE148315 | 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 long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation

Project description:The imprinted Dlk1-Dio3 domain comprises the developmental genes Dlk1 and Rtl1, which are silenced on the maternal chromosome in different cell types. On this parental chromosome, the domain’s imprinting control region activates a polycistron that produces the lncRNA Meg3 and many miRNAs (Mirg) and C/D-box snoRNAs (Rian). Although Meg3 lncRNA is nuclear and associates with the maternal chromosome, it is unknown whether it controls gene repression in cis. We created mouse embryonic stem cells (mESCs) that carry an ectopic poly(A) signal, reducing RNA levels along the polycistron, and generated Rian-/- mESCs as well. Upon ESC differentiation, we found that Meg3 lncRNA (but not Rian) is required for Dlk1 repression on the maternal chromosome. Biallelic Meg3 expression acquired through CRISPR-mediated demethylation of the paternal Meg3 promoter led to biallelic Dlk1 repression, and to loss of Rtl1 expression. lncRNA expression also correlated with DNA hypomethylation and CTCF binding at the 5’-side of Meg3. Using Capture Hi-C, we found that this creates a Topologically Associating Domain (TAD) organization that brings Meg3 close to Dlk1 on the maternal chromosome. The requirement of Meg3 for gene repression and TAD structure may explain how aberrant MEG3 expression at the human DLK1-DIO3 locus associates with imprinting disorders.

2024-03-28 | GSE207166 | GEO

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.

2018-04-10 | GSE99903 | GEO

Analysis of experience-regulated transcriptome and imprintome during critical periods of mouse visual system development

Project description:Visual system development is light-experience dependent, which strongly implicates epigenetic mechanisms in light-regulated maturation. Among many epigenetic processes, genomic imprinting is an epigenetic mechanism through which monoallelic gene expression occurs in a parent-of-origin-specific manner. It is unknown if genomic imprinting contributes to visual system development. We profiled the transcriptome and imprintome during critical periods of mouse visual system development under normal- and dark-rearing conditions using B6/CAST F1 hybrid mice. We identified experience-regulated, isoform-specific, and brain region-specific imprinted genes. We also found imprinted microRNAs were predominantly clustered into the Dlk1-Dio3 imprinted locus with light experience affecting some imprinted miRNA expression. Our findings provide the first comprehensive analysis of light-experience regulation of the transcriptome and imprintome during critical periods of visual system development. Our results may contribute to therapeutic strategies for visual impairments and circadian rhythm disorders resulting from a dysfunctional imprintome.

2018-04-17 | GSE98117 | GEO

Differentiation of human parthenogenetic pluripotent stem cells reveals multiple tissue and isoform specific imprinted transcripts

Project description:Parental imprinting results in a monoallelic parent-of-origin dependent gene expression. However, many imprinted genes identified by differential methylation do not exhibit complete monoallelic expression. Previous studies demonstrated a complex tissue-dependent expression patterns for some imprinted genes. Still, the complete magnitude of this phenomenon remains largely unknown. Differentiating human parthenogenetic induced pluripotent stem cells into different cell types and combining DNA methylation with novel 5' RNA sequencing methodology, enabled us to identify tissue- and isoform-dependent imprinted genes in a genome wide manner. We show that nearly half of all imprinted genes expresses both biallelic and monoallelic isoforms, that are controlled by tissue specific alternative promoters. This study provides the first global analysis of tissue-specific imprinting in humans, and implies that alternative promoters are central in the regulation of imprinted genes. Gene expression analysis was performed on a total of 6 human cell lines, including 4 iPSCs differentiated to neural progenitors and sorted using NCAM1 (2 control and 2 Parthenogenetic), and 2 iPSCs differentiated to endodermal progenitors (1 Control and 1 Parthenogenetic)

2016-07-03 | E-GEOD-65002 | biostudies-arrayexpress

Loss of non-coding RNA expression from the DLK1-DIO3 imprinted locus correlates with reduced neural differentiation potential in human embryonic stem cell lines

Project description:Pluripotent stem cells are increasingly used for therapeutic models, including transplantation of neural progenitors derived from human embryonic stem cells (hESCs). Recently, long non-coding RNAs (lncRNAs), including Maternally Expressed Gene 3 (MEG3) that is derived from DLK1-DIO3 imprinted locus, were found to be expressed during neural developmental events. Their deregulations are associated with various neurological diseases. The DLK1-DIO3 imprinted locus encodes abundant non-coding RNAs (ncRNAs) that are regulated by differential methylation on the locus. The aim of our research is to study the correlation between the DLK1-DIO3 derived ncRNAs and the capacity of hESC neural lineage differentiation. We classified hESCs into MEG3-ON and MEG3-OFF based on the expression levels of MEG3 as well as its downstream miRNAs by qRT-PCR. Initial embryoid body (EB) formation was conducted to examine the three germ layer differentiation ability. cDNA microarray was used to analyze the gene expression profiles of hESCs. Directed neural lineage differentiation was performed, followed by analysis of neural lineage marker expression levels and neurite formation via qRT-PCR and immunocytochemistry methods to investigate the capacity of neural differentiation in MEG3-ON and MEG3-OFF hESCs To study the correlations between the DLK1-DIO3 derived ncRNAs and differentiation capacity of hESC toward neural lineage, we classified hESCs into MEG3-ON and MEG3-OFF based on the expression levels of MEG3 by qRT-PCR and validated the methylation patterns of DLK1-DIO3 locus by bisulfite-sequencing. Then we conducted transcriptome analysis of these two groups of hESCs by cDNA microarray. This set contained 12 microarray samples, including 4 MEG3-ON hESCs, 7 MEG3-OFF hESCs, and 1 embryoid body as the negative control of pluripotentcy for pluritest.

2014-11-05 | E-GEOD-58809 | biostudies-arrayexpress

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

BALANCED GENE DOSAGE CONTROL RATHER THAN PARENTAL ORIGIN UNDERPINS GENOMIC IMPRINTING

Project description:Mammalian parental imprinting represents an exquisite form of epigenetic control regulating the parent-specific monoallelic expression of genes in clusters. While imprinting perturbations are widely associated with developmental abnormalities, the intricate regional interplay between imprinted genes makes interpreting the contribution of gene dosage effects to phenotypes a challenging task. Using mouse models with distinct deletions in an intergenic region controlling imprinting across the Dlk1-Dio3 domain, we link changes in genetic and epigenetic states to allelic-expression and phenotypic outcome in vivo. This determined how hierarchical interactions between regulatory elements orchestrate robust parent-specific expression, with implications for non-imprinted gene regulation. Strikingly, flipping imprinting on the parental chromosomes by crossing genotypes of complete and partial intergenic element deletions, rescues the lethality of each deletion on its own. Our work indicates that parental origin of an epigenetic state is irrelevant as long as appropriate balanced gene expression is established and maintained at imprinted loci.

2022-07-09 | GSE207600 | GEO

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