Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa, Shin-ichi; Sasaki, Hidetada

doi:10.1038/jhg.2011.151

Cited by 80 publications

(63 citation statements)

References 106 publications

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“…Because allelic DNA methylation of ICRs is acquired during gametogenesis, ICRs are also called germline differentially methylated regions (gDMRs) (Ferguson-Smith, 2011;Kelsey and Feil, 2013;Tomizawa and Sasaki, 2012). Recent genome-wide profiling has, however, revealed that the number of oocyte-or sperm-specific methylated genomic regions is far more than that of the known ICRs (Kobayashi et al, 2012;Smallwood et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

et al. 2015

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Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gametespecific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A-and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5′ segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis.

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Section: Introductionmentioning

confidence: 99%

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

et al. 2015

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“…The process of robust erasure and resetting of the epigenome in early PGCs also ensures that aberrant epigenetic information is not transmitted to the offspring. Nonetheless, there are recent reports suggesting that environmental factors can induce epigenetic changes that can be transmitted through the germline to subsequent generations with detrimental consequences (reviewed by Tomizawa and Sasaki, 2012). Studies on the germ cell lineage might test the validity of these claims or provide the mechanistic basis for them.…”

Section: Introductionmentioning

confidence: 99%

How to make a primordial germ cell

2014

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Primordial germ cells (PGCs) are the precursors of sperm and eggs, which generate a new organism that is capable of creating endless new generations through germ cells. PGCs are specified during early mammalian postimplantation development, and are uniquely programmed for transmission of genetic and epigenetic information to subsequent generations. In this Primer, we summarise the establishment of the fundamental principles of PGC specification during early development and discuss how it is now possible to make mouse PGCs from pluripotent embryonic stem cells, and indeed somatic cells if they are first rendered pluripotent in culture.

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“…Disruption of imprinted expression in humans leads to several developmental disorders and may contribute to cancer (Lee and Bartolomei, 2013;Soellner et al, 2016;Tomizawa and Sasaki, 2012;Wilkins and Úbeda, 2011). One of the earliest examples of an imprinting disorder is Beckwith-Wiedemann syndrome (BWS), a generalized overgrowth and cancer predisposition condition (Weksberg et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome

et al. 2017

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The maternally methylated KvDMR1 ICR regulates imprinted expression of a cluster of maternally expressed genes on human chromosome 11p15.5. Disruption of imprinting leads to BeckwithWiedemann syndrome (BWS), an overgrowth and cancer predisposition condition. In the majority of individuals with BWS, maternal-specific methylation at KvDMR1 is absent and genes under its control are repressed. We analyzed a mouse model carrying a poly(A) truncation cassette inserted to prevent RNA transcripts from elongation through KvDMR1. Maternal inheritance of this mutation resulted in absence of DNA methylation at KvDMR1, which led to biallelic expression of Kcnq1ot1 and suppression of maternally expressed genes. This study provides further evidence that transcription is required for establishment of methylation at maternal gametic DMRs. More importantly, this mouse model recapitulates the molecular phenotypic characteristics of the most common form of BWS, including loss of methylation at KvDMR1 and biallelic repression of Cdkn1c, suggesting that deficiency of maternal transcription through KvDMR1 may be an underlying cause of some BWS cases.

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Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Cited by 80 publications

References 106 publications

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

De novoDNA methylation through 5'-segment of theH19ICR maintains its imprint during early embryogenesis

How to make a primordial germ cell

Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome

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