Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes

Wossidlo, Mark; Arand, Julia; Sebastiano, Vittorio; Lepikhov, Konstantin; Boiani, Michele; Reinhardt, Richard; Schöler, Hans R.; Walter, Jörn

doi:10.1038/emboj.2010.80

Cited by 223 publications

(244 citation statements)

References 57 publications

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“…However, how the expression of TEs in early preimplantation embryos is controlled remains unknown. Based on the observations that: (1) CpG sites in TEs are highly methylated in sperm genome and are demethylated after fertilization [24][25][26]; (2) the hypomethylated state of these CpG sites is maintained during preimplantation development [25], it is assumed that removal of paternal DNA methylation contributes to TE activation. In this study, we tested this assumption by evaluating the role of Tet3-mediated 5mC oxidation in TE activation.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

2012

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The methylation state of the paternal genome is rapidly reprogrammed shortly after fertilization. Recent studies have revealed that loss of 5-methylcytosine (5mC) in zygotes correlates with appearance of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). This process is mediated by Tet3 and the 5mC oxidation products generated in zygotes are gradually lost during preimplantation development through a replicationdependent dilution process. Despite these findings, the biological significance of Tet3-mediated oxidation of 5mC to 5hmC/5fC/5caC in zygotes is unknown. DNA methylation plays an important role in silencing gene expression including the repression of transposable elements (TEs). Given that the activation of TEs during preimplantation development correlates with loss of DNA methylation, it is believed that paternal DNA demethylation may have an important role in TE activation. Here we examined this hypothesis and found that Tet3-mediated 5mC oxidation does not have a significant contribution to TE activation. We show that the expression of LINE-1 (long interspersed nucleotide element 1) and ERVL (endogenous retroviruses class III) are activated from both paternal and maternal genomes in zygotes. Inhibition of 5mC oxidation by siRNA-mediated depletion of Tet3 affected neither TE activation, nor global transcription in zygotes. Thus, our study provides the first evidence demonstrating that activation of both TEs and global transcription in zygotes are independent of Tet3-mediated 5mC oxidation.

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Section: Introductionmentioning

confidence: 99%

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

2012

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“…Eggs and oocytes also possess active DNA demethylation activity, which is a requirement for the transcriptional reactivation of silenced genes (for example, OCT4); this activity is observed after nuclear transfer [41][42][43][44] , as well as in cell fusion to ES cells 45 . Two examples of enzymes that are thought to play a part in active DNA demethylation are growth arrest and DNA damage-inducible 45α (GADD45α) 42 and activation-induced deaminase (AID) 45 .…”

Section: Histone and Dna Modificationsmentioning

confidence: 99%

Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process?

Jullien

Pasque²,

Halley-Stott³

et al. 2011

Nat Rev Mol Cell Biol

105

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Differentiated cells can be experimentally reprogrammed back to pluripotency by nuclear transfer, cell fusion or induced pluripotent stem cell technology. Nuclear transfer and cell fusion can lead to efficient reprogramming of gene expression. The egg and oocyte reprogramming process includes the exchange of somatic proteins for oocyte proteins, the post-translational modification of histones and the demethylation of DNA. These events occur in an ordered manner and on a defined timescale, indicating that reprogramming by nuclear transfer and by cell fusion rely on deterministic processes.The remarkable stability of cell differentiation under normal conditions can be reversed experimentally by nuclear transfer, cell fusion and induced pluripotent stem (iPS) cell technology [1][2][3][4][5] . This provides an opportunity to generate pluripotent embryonic cells from adult cells of the same individual and hence opens the possibilit y of cell replacement without the need for immunosuppression.iPS cell technology makes use of the overexpression of transcription factors (FIG. 1a) and has been extensively reviewed, so it is not discussed in detail [6][7][8][9] . To generate entirely unrelated cell types by iPS cell technology, treated cells must be grown for multiple cell divisions over a long period of time (up to 3 weeks). By contrast, nuclear transfer and cell fusion do not involve the overexpression of new genes, and instead make use of natura components present in eggs and some early embryos to initiate new transcription.There are two kinds of nuclear transfer experiments: egg-NT involves the transfer of a single somatic nucleus to an unfertilize d enucleated egg (in both mammals and amphibians) 1 (FIG. 1b); and ooc-NT involves the transplantation of multiple somatic cell nuclei into the germinal vesicle (the nucleus) of a growing meiotic prophase amphibian oocyte (an immature egg) 10 (FIG. 1c). Note that the terms egg and oocyte refer to different developmental stages in amphibians and mammals: amphibian eggs are in metaphase II of meiosis, which is equivalent to mouse metaphase II stage oocytes, whereas their immediate precursors, oocytes, are blocked in meiotic prophase I, which is equivalent to mouse germinal vesicle stage oocytes.© 2011 Macmillan Publishers Limited. All rights reserved Correspondence to J.B.G.j.gurdon@gurdon.cam.ac.uk. Competing interests statementThe authors declare no competing financial interests. There are important differences between the two types of nuclear transfer experimen t. Extensive cell division takes place in egg-NT experiments, and functional new cell types appear as the nuclear transplant embryo develops. By contrast, in ooc-NT experiments, no new cell types are formed, and neither the oocyte nor the introduced nuclei divide, but there is a direct transition from nuclei of differentiated cells to reprogrammed nuclei that transcribe pluripotency genes. Analysis of the mechanism of reprogramming (which involves transcription of pluripotency and other genes) in egg-NT expe...

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“…Sperm DNA, which is more methylated than oocyte DNA (Kobayashi et al 2012;Smallwood and Kelsey 2012) undergoes active demethylation during the first cell cycle. This process is driven, in part, by ten-eleven translocation (TET) methylcytosine dioxygenase 3 (TeT3), which catalyses the conversion of methylated cytosines into hydroxymethyl cytosines (Gu et al 2010;Iqbal et al 2011) before the start of DNA replication (Wossidlo et al 2010). Paternal DNA demethylation is an essential step in early development, because most TeT3 mutant embryos do not survive development to term (Gu et al 2010).…”

Section: Recent Advances In Epigeneticsmentioning

confidence: 99%

Epigenetics and developmental programming of welfare and production traits in farm animals

Sinclair

Rutherford

Wallace

et al. 2016

Reprod. Fertil. Dev.

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Abstract. The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the 'developmental origins of health and disease' or 'DOHaD' hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems.

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Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes

Cited by 223 publications

References 57 publications

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation

Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process?

Epigenetics and developmental programming of welfare and production traits in farm animals

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