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Targets and dynamics of promoter DNA methylation during early mouse development

Nature Genetics volume 42, pages 1093–1100 (2010)Cite this article

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Abstract

DNA methylation is extensively reprogrammed during the early phases of mammalian development, yet genomic targets of this process are largely unknown. We optimized methylated DNA immunoprecipitation for low numbers of cells and profiled DNA methylation during early development of the mouse embryonic lineage in vivo. We observed a major epigenetic switch during implantation at the transition from the blastocyst to the postimplantation epiblast. During this period, DNA methylation is primarily targeted to repress the germline expression program. DNA methylation in the epiblast is also targeted to promoters of lineage-specific genes such as hematopoietic genes, which are subsequently demethylated during terminal differentiation. De novo methylation during early embryogenesis is catalyzed by Dnmt3b, and absence of DNA methylation leads to ectopic gene activation in the embryo. Finally, we identify nonimprinted genes that inherit promoter DNA methylation from parental gametes, suggesting that escape of post-fertilization DNA methylation reprogramming is prevalent in the mouse genome.

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Figure 1: Profiling of DNA methylation during early mouse embryogenesis.
Figure 2: De novo CpG island methylation in epiblast cells.
Figure 3: Promoter DNA methylation at hematopoietic genes is erased during hematopoietic differentiation.
Figure 4: Inheritance of promoter DNA methylation from oocytes at nonimprinted genes.
Figure 5: Promoter DNA methylation mediated by Dnmt3b maintains gene repression in vivo.

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Acknowledgements

We thank R. Vicente for assistance with the flow cytometry, T. Gostan for help with R programming, and E. Posfai and R. Hirasawa for advice on embryo dissection. This research was supported by the Epigenome NoE (LSHG-CT-2006-037415), Novartis Research Foundation, Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche (ANR-07-BLAN-0052-02), Association pour la Recherche sur le Cancer (ARC contract 4868) and European Chemical Industry Council (CEFIC) Long Research Initiative (LRI-EMSG49-CNRS-08).

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Authors and Affiliations

  1. Institute of Molecular Genetics, Centre National de la Recherche Scientifique (CNRS) UMR 5535, Université Montpellier 2, Université Montpellier 1, Montpellier, France

    Julie Borgel, Sylvain Guibert, Thierry Forné & Michael Weber

  2. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan

    Yufeng Li, Hatsune Chiba & Hiroyuki Sasaki

  3. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    Dirk Schübeler

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  1. Julie Borgel
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Contributions

J.B. performed all experiments and data analysis and contributed to the writing of the manuscript. S.G. developed R scripts and participated in data analysis. Y.L., H.C. and H.S. prepared samples from Dnmt mutant embryos. D.S. and T.F. participated in the study design and writing of the manuscript. M.W. designed and supervised the study, participated in data analysis and wrote the manuscript.

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Correspondence to Michael Weber.

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Supplementary Figures 1–13 and Supplementary Table 2 (PDF 4400 kb)

Supplementary Table 1

Genes with methylated promoters identified in early mouse embryos. (ZIP 70 kb)

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Borgel, J., Guibert, S., Li, Y. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42, 1093–1100 (2010). https://doi.org/10.1038/ng.708

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