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Absence of genome-wide changes in DNA methylation during development of the zebrafish

Nature Genetics volume 23, pages 139–140 (1999)Cite this article

CpGs in the vertebrate genome are targets for DNA cytosine methyltransferases. Methylation leads to local transcriptional repression and is essential for normal development in the mouse1. Both gametogenesis and early embryogenesis of mouse are accompanied by changes in global levels of DNA methylation2,3. Methylation levels are lowest in blastocyst DNA, but are restored to normal by the time of implantation. Several single-copy genes, repetitive sequences and transgenes have been shown to lose methylation in the early embryonic stages4. Notably, some imprinted regions have been shown to remain highly methylated through the blastocyst stage despite global hypomethylation4,5.

Our results indicate that development of a complex vertebrate need not involve global demethylation of the genome during embryogenesis. We did not detect passive loss of DNA methylation over several cell divisions, as seen in the mouse3. In theory, sudden global demethylation/de novo methylation may have escaped detection, but there is no reliable precedent for this. Why should the methylation status of zebrafish embryonic DNA be different from that of the mouse? There are several possible explanations. Two phenomena associated with DNA methylation in mammals, parental imprinting and X inactivation, may not occur in zebrafish. No endogenous parentally imprinted genes have been described, and if imprinting were to exist, it is unlikely to affect essential genes, as androgenetic and gynogenetic zebrafish are viable12. In the mouse, however, androgenetic and gynogenetic embryos fail to develop to term13,14. One hypothesis is that imprinting is a mammalian phenomenon and establishes the fetal-maternal relationship and development of the placenta15. There may be a relationship between embryonic loss of methylation and the requirement for an imprinted genome in the mouse. Parental alleles of some imprinted genes are differentially marked by methylation and a mechanism exists to maintain this mark in the preimplantation mouse embryo when global demethylation takes place4,5,15. Low Dnmt activity at this time might prevent accidental de novo methylation of non-methylated (but perhaps silent) parental alleles without jeopardizing maintenance of the imprinting signal. Alternatively, loss of methylation from the mouse blastocyst genome may serve to erase methylation from the gene Xist, enabling random X inactivation to proceed in the post-implantation embryo15. In the absence of imprinting and X inactivation, the zebrafish would not need either of these mechanisms. A third possibility is raised by the observation that the mammalian genome (unlike that of other vertebrates) is activated very early during development16, suggesting that the loss of methylation from the mouse embryo may facilitate the early activation of zygotic transcription. Other vertebrates, such as the zebrafish, may not require input from the zygotic genome until later, and instead rely on maternal factors derived from the oocyte. In the meantime, the silent embryonic genome remains methylated.

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Figure 1: High levels of DNA methylation in gametes and early embryonic stages of zebrafish.
Figure 2: Average methylation levels at three single-copy genes during early development of the zebrafish.

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Acknowledgements

We thank J. Lewis, S. Massey and P. Currie for staged zebrafish embryos; A. Greig and J. Davidson for technical support; and S. Tweedie for critical reading of the manuscript. This work was supported by The Wellcome Trust and The Howard Hughes Medical Institute

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  1. Institute of Cell and Molecular Biology, University of Edinburgh, The King's Buildings,, Edinburgh, EH9 3JR, Scotland

    Donald Macleod, Victoria H. Clark & Adrian Bird

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Correspondence to Donald Macleod.

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Macleod, D., Clark, V. & Bird, A. Absence of genome-wide changes in DNA methylation during development of the zebrafish. Nat Genet 23, 139–140 (1999). https://doi.org/10.1038/13767

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