Deletion of Gtl2 , imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice

Takahashi, Nozomi; Okamoto, Akira; Kobayashi, Ryota; Shirai, Motomu; Obata, Yayoi; Ogawa, Hidehiko; Sotomaru, Yusuke; Kono, Toru

doi:10.1093/hmg/ddp108

Cited by 101 publications

(105 citation statements)

References 45 publications

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“…Our histological findings in mice with maternal transmission of the Gtl2 deletion suggest arrest or delay in progression from the myotube stage in our mice, which may contribute to their lack of survival through the perinatal period. Takahashi et al (Takahashi et al, 2009) reported that deletion of both Gtl2 and its DMR abolished Gtl2 expression, but retained various levels of expression of other MEGs and did not significantly affect expression of PEGs. Interestingly, mice carrying this maternal deletion have a much milder phenotype; they were born alive and lived up to 4 weeks after birth (Takahashi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

et al. 2010

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SUMMARYThe Dlk1-Gtl2 imprinting locus is located on mouse distal chromosome 12 and consists of multiple maternally expressed noncoding RNAs and several paternally expressed protein-coding genes. The imprinting of this locus plays a crucial role in embryonic development and postnatal growth. At least one cis-element, the intergenic differentially methylated region (IG-DMR) is required for expression of maternally expressed genes and repression of silenced paternally expressed genes. The mechanism by which the IG-DMR functions is largely unknown. However, it has been suggested that the unmethylated IG-DMR acts as a positive regulator activating expression of non-coding RNAs. Gtl2 is the first non-coding RNA gene downstream of the IG-DMR. Although its in vivo function in the mouse is largely unknown, its human ortholog MEG3 has been linked to tumor suppression in human tumorderived cell lines. We generated a knockout mouse model, in which the first five exons and adjacent promoter region of the Gtl2 gene were deleted. Maternal deletion of Gtl2 resulted in perinatal death and skeletal muscle defects, indicating that Gtl2 plays an important role in embryonic development. The maternal deletion also completely abolished expression of downstream maternally expressed genes, activated expression of silenced paternally expressed genes and resulted in methylation of the IG-DMR. By contrast, the paternal inherited deletion did not have this effect. These data strongly indicate that activation of Gtl2 and its downstream maternal genes play an essential role in regulating Dlk1-Gtl2 imprinting, possibly by maintaining active status of the IG-DMR.

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Section: Discussionmentioning

confidence: 99%

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

et al. 2010

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“…They localize to the imprinted Dlk1-Dio3 gene cluster on mouse chromosome 12 and are maternally expressed. Its aberrant regulation is implicated in murine impaired development [29]. Epigenetically, the locus is fully methylated in many iPSC lines, while some lines have only one allele silenced, as is the case in ESC.…”

Section: Transcriptional Comparison Of Esc and Ipscmentioning

confidence: 99%

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

2011

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“…2C). Deletion of the Meg3 promoter DMR and the first few exons of Meg3 also interferes with ncRNA transcription with reciprocal effects on protein-encoding gene expression (Takahashi et al 2009; Fig. 2D).…”

Section: Regulatory Regionsmentioning

confidence: 99%

Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models

Howard

Charalambous

2015

Reproduction

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Uniparental inheritance of chromosome 14q32 causes developmental failure during gestation and early postnatal development due to mis-expression of a cluster of imprinted genes under common epigenetic control. Two syndromes associated with chromosome 14q32 abnormalities have been described, Kagami-Ogata and Temple syndromes. Both of these syndromes are characterised by specific impairments of intrauterine development, placentation and early postnatal survival. Such abnormalities arise because the processes of intrauterine growth and postnatal adaptation are critically modulated by the dosage of imprinted genes in the chromosome 14q32 cluster. Much of our understanding of how the imprinted genes in this cluster are regulated, as well as their individual functions in the molecular pathways controlling growth and postnatal adaptation, has come from murine models. Mouse chromosome 12qF1 contains an imprinted region syntenic to human chromosome 14q32, collectively referred to as the Dlk1-Dio3 cluster. In this review, we will summarise the wealth of information derived from animal models of chromosome 12 imprinted gene mis-regulation, and explore the relationship between the functions of individual genes and the phenotypic result of their mis-expression. As there is often a considerable overlap between the functions of genes in the Dlk1-Dio3 cluster, we propose that the expression dosage of these genes is controlled by common regulatory mechanisms to co-ordinate the timing of growth and postnatal adaptation. While the diseases associated with mis-regulated chromosome 14 imprinting are rare, studies carried out in mice on the functions of the affected genes as well as their normal regulatory mechanisms have revealed new mechanistic pathways for the control of growth and survival in early life.Reproduction (2015) 149 R237-R249

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Deletion of Gtl2 , imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice

Cited by 101 publications

References 45 publications

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models

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