Novel Imprinted DLK1/GTL2 Domain on Human Chromosome 14 Contains Motifs that Mimic Those Implicated in IGF2/H19 Regulation

Wylie, Andrew; Murphy, Susan K.; Orton, Terry C.; Jirtle, Randy L.

doi:10.1101/gr.161600

Cited by 262 publications

(231 citation statements)

References 36 publications

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“…This is consistent with the published data on the genomic imprinting of DLK1 in other developing tissues. 6 Likewise, allelic quantification of DIO3 was performed in eight samples carrying the DIO3 G/T genotype (Figure 1c). On average, the degree of monoallelic expression for DIO3 was 74% (Figures 1c and d; Representative pyrograms for DLK1 and DIO3 allele quantification in two of the samples analyzed are shown in Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…5 The imprinted DLK1-DIO3 region is located in the distal arm of human chromosome 14. 6 Patients with maternal or paternal UPD of human chromosome 14 (UPD14; named Temple and Kagami-Ogata syndromes, respectively) present with distinct developmental abnormalities, including hydrocephalus, hypotonia, abnormal growth, mental retardation, craniofacial dismorphisms, altered puberty onset, abnormal rib cage and others. 7,8 Several genes within this region, including DLK1 and MEG3, are subject to genomic imprinting, that is, they exhibit a high degree of monoallelic expression.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Several genes within this region, including DLK1 and MEG3, are subject to genomic imprinting, that is, they exhibit a high degree of monoallelic expression. 6 However, it is uncertain whether DIO3 is imprinted. Studies on the placentas of infants with UPD of chromosome 14 and related epimutations suggest that DIO3 is not imprinted in this tissue in humans.…”

Section: Introductionmentioning

confidence: 99%

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Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

et al. 2016

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Individuals with uniparental disomy of chromosome 14 (Temple and Kagami-Ogata syndromes) exhibit a number of developmental abnormalities originating, in part, from aberrant developmental expression of imprinted genes in the DLK1-DIO3 cluster. Although genomic imprinting has been reported in humans for some genes in the cluster, little evidence is available about the imprinting status of DIO3, which modulates developmental exposure to thyroid hormones. We used pyrosequencing to evaluate allelic expression of DLK1 and DIO3 in cDNAs prepared from neonatal foreskins carrying single-nucleotide polymorphisms (SNPs) in the exonic sequence of those genes, and hot-stop PCR to quantify DIO3 allelic expression in cDNA obtained from a skin specimen collected from an adult individual with known parental origin of the DIO3 SNP. In neonatal skin, DLK1 and DIO3 both exhibited a high degree of monoallelic expression from the paternal allele. In the adult skin sample, the allele preferentially expressed is that inherited from the mother, although a different, larger DIO3 mRNA transcript appears the most abundant at this stage. We conclude that DIO3 is an imprinted gene in humans, suggesting that alterations in thyroid hormone exposure during development may partly contribute to the phenotypes associated with uniparental disomy of chromosome 14.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

et al. 2016

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“…The 14q32 region has been associated with imprinting disorders 35 and tumorigenesis. 36 In particular, this genomic area harbors three differentially methylated regions 37,38 described to coordinately regulate (1) the paternally expressed genes DLK1 and RTL1 (retrosposon-like1) and (2) the maternally expressed genes MEG3 (long intergenic non-protein coding RNA 23 or GTL2), RTL-antisense transcript, MEG8, MEG9, and several polyadenylated C/D box small nucleolar (sno)RNAs 39,40 and microRNAs 20,[40][41][42][43] ( Figure 2, Tables S6 and S7). From our analysis, we validated the known imprinting statuses of MEG3, MEG8, MEG9, DLK1, and RTL-antisense transcripts (Tables S7), but the DIO3 and RTL1 genes were not detectable in fibroblasts.…”

Section: Characterization Of Known Imprinted Genes In Singlecell Fibrmentioning

confidence: 99%

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

Santoni

Stamoulis

Garieri

et al. 2017

The American Journal of Human Genetics

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Genomic imprinting results in parental-specific gene expression. Imprinted genes are involved in the etiology of rare syndromes and have been associated with common diseases such as diabetes and cancer. Standard RNA bulk cell sequencing applied to whole-tissue samples has been used to detect imprinted genes in human and mouse models. However, lowly expressed genes cannot be detected by using RNA bulk approaches. Here, we report an original and robust method that combines single-cell RNA-seq and whole-genome sequencing into an optimized statistical framework to analyze genomic imprinting in specific cell types and in different individuals. Using samples from the probands of 2 family trios and 3 unrelated individuals, 1,084 individual primary fibroblasts were RNA sequenced and more than 700,000 informative heterozygous single-nucleotide variations (SNVs) were genotyped. The allele-specific coverage per gene of each SNV in each single cell was used to fit a beta-binomial distribution to model the likelihood of a gene being expressed from one and the same allele. Genes presenting a significant aggregate allelic ratio (between 0.9 and 1) were retained to identify of the allelic parent of origin. Our approach allowed us to validate the imprinting status of all of the known imprinted genes expressed in fibroblasts and the discovery of nine putative imprinted genes, thereby demonstrating the advantages of single-cell over bulk RNA-seq to identify imprinted genes. The proposed single-cell methodology is a powerful tool for establishing a cell type-specific map of genomic imprinting.

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“…In addition, it is an imprinted gene transcribed from the paternal allele (Schmidt et al, 2000;Takada et al, 2000Takada et al, , 2002Wylie et al, 2000).…”

mentioning

confidence: 99%

DLK1: increased expression in gliomas and associated with oncogenic activities

et al. 2006

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DLK1 (delta-like) is a transmembrane and secreted protein in the epidermal growth factor-like homeotic family. Although expressed widely during embryonic development, only a few tissues retain the expression in adults. Neuroendocrine tumors often highly express this protein; therefore, we hypothesized that brain tumors might also express it. This study found that the expression of DLK1 in gliomas was higher than that in normal brain (Po0.05). After stable transfection of a DLK1 cDNA expression vector into GBM cell lines, their proliferation was increased. Furthermore, they lost contact inhibition, had enhanced anchorage-independent growth in soft agar, and had significantly greater capacity to migrate. Western blot studies showed that expression of cyclin D1, CDK2, and E2F4 were increased, and Rb levels were decreased in these cells. DLK1 was found on the cell surface and secreted in the medium from the transfected GBM cells. DLK1-enriched condition medium stimulated the growth of glioblastoma multiforme cell lines and explants. DLK1 antibody blocked cell growth stimulated by DLK1. In summary, these results suggest that DLK1 may play a role in the formation or progression of gliomas.

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Novel Imprinted DLK1/GTL2 Domain on Human Chromosome 14 Contains Motifs that Mimic Those Implicated in IGF2/H19 Regulation

Cited by 262 publications

References 36 publications

Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

DLK1: increased expression in gliomas and associated with oncogenic activities

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