A microRNA cluster in the DLK1-DIO3 imprinted region on chromosome 14q32.2 in hepatoblastoma
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ABSTRACT:
PROVIDER: PRJNA641410 | ENA |
REPOSITORIES: ENA
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Project description:Using array-based expression analysis on formalin-fixed paraffin-embedded tissues, we aimed to identify miRNA signatures that can discriminate between lung metastatic tumors, primary tumors (fetal and embryonal subtypes) and nontumorous surrounding livers. A large cluster of microRNAs and snoRNAs located within the 14q32.2 DLK1-DIO3 region showed a strikingly upregulated expression pattern in HB tumors, especially metastatic tumors, compared to normal liver tissues.
2020-11-20 | GSE153089 | GEO
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
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.
2014-04-03 | GSE56136 | GEO
Project description:Our previous study demonstrated a significant upregulation of a large set of miRNAs at the genomic imprinted Dlk1-Dio3 locus in lymphocytes of diverse murine lupus-prone strains. The upregulation of Dlk1-Dio3 miRNAs in lupus-prone mice is correlated with the global DNA hypomethylation. In this study, by performing genome-wide DNA methylation analysis, we reported that Dlk1-Dio3 genomic region in CD4+ T cells of MRL/lpr mice was hypomethylated, further linking hypomethylation to the increased expression of Dlk1-Dio3 miRNAs in lupus. Then, we assessed the gene expression levels of enzymes that either write (DNA methyltransferases, DNMTs) or erase DNA methylation (Ten-eleven translation proteins, TETs) to understand the molecular contributor to the DNA hypomethylation in MRL/lpr CD4+ T cells. The expression levels of Dnmt1, Dnmt3b, Tet1, and Tet2 were significantly increased in CD4+ T cells of MRL/lpr mice, as well as in B6/lpr and B6.sle123 mice, compared to their respective control mice. These data indicate the significant involvement of the TETs-mediated active demethylation pathway rather than reduced DNMTs-mediated passive demethylation pathway in the hypomethylation of murine lupus CD4+ T cells. The transcription factor, early growth response 2 (EGR2) is critically involved in regulating T cell functions and autoimmunity. In this research, we found that Egr2 deletion in B6/lpr mice notably reduced methylation-sensitive Dlk1-Dio3 cluster miRNAs expression in CD4+ T cells. Surprisingly, even though EGR2 has been shown to induce DNA demethylation by recruiting TET2, we found that deleting Egr2 in B6/lpr mice induced a higher number of hypomethylated DMRs than hypermethylated DMRs at either whole genome or the Dlk1-Dio3 locus in CD4+ T cells of B6/lpr mice. These data are the first finding on the positive role of EGR2 on the expression of Dlk1-Dio3 cluster miRNAs in lupus mice. Given that Dlk1-Dio3 miRNAs target the major signaling pathways in autoimmunity, these data provide a new perspective in understanding the potential pathogenic role of upregulated EGR2 in lupus.
2023-12-04 | GSE242955 | GEO
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
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
2014-12-01 | GSE58508 | GEO
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
2014-11-05 | GSE58809 | GEO
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
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
Project description:To investigate the collective role of the Dlk1-Dio3 ncRNA cluster in myogenesis, we developed two stable CRISPR-Cas9 gene-edited C2C12 skeletal muscle cell lines, Meg3-proximal cis-acting sequence (Meg3-CAS or 2-4) to over-express and Meg3-transcription start site (Meg3-TSS or 2-7) to under-express the entire mega-cluster of Dlk1-Dio3 ncRNAs. Mutations affecting the dosage of all ncRNAs expressed from the Dlk1-Dio3 locus cause profound changes in myoblast fusion and differentiation. To evaluate genome-wide perturbations in chromatin accessibility we evaluated specific histone lysine modifications, inducing the repressive histone mark, H3K27me3, and the activating mark, H3K4me3
2024-10-31 | GSE272974 | GEO