Abstract

Once fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are activated by a conserved homeodomain-containing transcription factor, DUX. However, Dux-knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by an unknown factor(s). Here we present multiple lines of evidence that the multicopy homeobox gene, Obox4, encodes a transcription factor that is highly expressed in mouse 2-cell embryos and redundantly drives ZGA. Genome-wide profiling revealed that OBOX4 specifically binds and activates MERVL LTRs as well as a subset of murine endogenous retroviruses with lysine tRNA primer (MERVK) LTRs. Depletion of Obox4 is tolerated by embryogenesis, whereas concomitant Obox4/Dux depletion markedly compromises embryonic development. Our study identified OBOX4 as a transcription factor that provides genetic redundancy to pre-implantation development.

Data availability

The RNA-seq and CUT&RUN-seq data generated in this study have been deposited at NCBI Gene Expression Omnibus (GEO) database under the accession code GSE196671.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Youjia Guo

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Tomohiro Kitano

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Kimiko Inoue

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Kensaku Murano

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Michiko Hirose

    Bioresource Engineering Division, RIKEN BioResource Research Center, Ibaraki, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Ten D Li

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Akihiko Sakashita

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Hirotsugu Ishizu

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Narumi Ogonuki

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Shogo Matoba

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Masayuki Sato

    Department of Molecular Biology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5484-4597
  12. Atsuo Ogura

    Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
    For correspondence
    ogura@rtc.riken.go.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0447-1988
  13. Haruhiko Siomi

    Department of Molecular Biology, Keio University, Tokyo, Japan
    For correspondence
    awa403@keio.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8690-3822

Funding

Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research in Innovative Areas,19H05753)

  • Haruhiko Siomi

Japan Agency for Medical Research and Development (Project to Elucidate and Control Mechanisms of Aging and Longevity)

  • Haruhiko Siomi

Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research in Innovative Areas,19H05758)

  • Atsuo Ogura

Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research KAKENHI,20K21507)

  • Kensaku Murano

Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research KAKENHI,22H02534)

  • Kimiko Inoue

Mochida Memorial Foundation for Medical and Pharmaceutical Research

  • Kensaku Murano

Sumitomo Foundation

  • Kensaku Murano

Keio University (Student Grant-in-Aid Program)

  • Youjia Guo

Japan Science and Technology Agency (Doctoral Program Student Support Fellowship)

  • Youjia Guo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Falong Lu, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, China

Ethics

Animal experimentation: All animal experiments were approved by the Animal Care and Use Committee of Keio University and the Animal Experimentation Committee at the RIKEN Tsukuba Institute and conducted in compliance with the Keio University Code of Research Ethics and the RIKEN's guiding principles. (License #11045-4) and the RIKEN's guiding principles (T2023-Jitsu015).

Version history

  1. Received: January 7, 2024
  2. Accepted: June 7, 2024
  3. Accepted Manuscript published: June 10, 2024 (version 1)

Copyright

© 2024, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Youjia Guo
  2. Tomohiro Kitano
  3. Kimiko Inoue
  4. Kensaku Murano
  5. Michiko Hirose
  6. Ten D Li
  7. Akihiko Sakashita
  8. Hirotsugu Ishizu
  9. Narumi Ogonuki
  10. Shogo Matoba
  11. Masayuki Sato
  12. Atsuo Ogura
  13. Haruhiko Siomi
(2024)
Obox4 promotes zygotic genome activation upon loss of Dux
eLife 13:e95856.
https://doi.org/10.7554/eLife.95856

Share this article

https://doi.org/10.7554/eLife.95856

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