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A unique regulatory phase of DNA methylation in the early mammalian embryo

Author

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  • Zachary D. Smith

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
    Harvard University, Cambridge, Massachusetts 02138, USA)

  • Michelle M. Chan

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Tarjei S. Mikkelsen

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA)

  • Hongcang Gu

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA)

  • Andreas Gnirke

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA)

  • Aviv Regev

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Alexander Meissner

    (Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
    Harvard University, Cambridge, Massachusetts 02138, USA)

Abstract

DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)—including many CpG island promoters—that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern.

Suggested Citation

  • Zachary D. Smith & Michelle M. Chan & Tarjei S. Mikkelsen & Hongcang Gu & Andreas Gnirke & Aviv Regev & Alexander Meissner, 2012. "A unique regulatory phase of DNA methylation in the early mammalian embryo," Nature, Nature, vol. 484(7394), pages 339-344, April.
    • Handle: RePEc:nat:nature:v:484:y:2012:i:7394:d:10.1038_nature10960
    DOI: 10.1038/nature10960
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    Cited by:

    1. Ariane Lismer & Sarah Kimmins, 2023. "Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Joseph L. Graves Jr., 2015. "Great Is Their Sin," The ANNALS of the American Academy of Political and Social Science, , vol. 661(1), pages 24-50, September.
    3. Allegra Angeloni & Skye Fissette & Deniz Kaya & Jillian M. Hammond & Hasindu Gamaarachchi & Ira W. Deveson & Robert J. Klose & Weiming Li & Xiaotian Zhang & Ozren Bogdanovic, 2024. "Extensive DNA methylome rearrangement during early lamprey embryogenesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Wenwen Li & Ann Van Soom & Luc Peelman, 2017. "Repeats as global DNA methylation marker in bovine preimplantation embryos," Czech Journal of Animal Science, Czech Academy of Agricultural Sciences, vol. 62(2), pages 43-50.

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