Obox4 promotes zygotic genome activation upon loss of Dux

Abstract
Data availability
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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

1. Guo Y
2. Kitano T
3. Siomi H
(2023) Obox4 secures zygotic genome activation upon loss of Dux
NCBI Gene Expression Omnibus, GSE196671.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE196671

The following previously published data sets were used

(2014) Single-cell RNA-Seq reveals dynamic, random monoallelic gene expression in mammalian cells
NCBI Gene Expression Omnibus, GSE45719.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE45719
1. Xiong Z
2. Xu K
3. Lin Z
4. Kong F
5. Wang Q
6. Quan Y
7. Li L
8. Xie W
(2022) Ultrasensitive Ribo-seq reveals translational landscapes during mammalian oocyte-to-embryo transition and pre-implantation development
NCBI Gene Expression Omnibus, GSE165782.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165782
1. Shen H
2. Yang M
3. Li S
4. Du P
(2021) Mouse totipotent stem cells captured and maintained through spliceosomal repression
NCBI Gene Expression Omnibus, GSE168728.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE168728
1. Chen Z
2. Zhang Y
(2019) Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development
NCBI Gene Expression Omnibus, GSE121746.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121746
1. Grun D
2. De Iaco A
(2019) RNAseq of DUX KO mouse 2-cell embryos
NCBI Gene Expression Omnibus, GSE141321.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE141321
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(2017) Conserved roles for murine mDUX and human DUX4 in activating cleavage stage genes and MERVL/HERVL retrotransposons
NCBI Gene Expression Omnibus, GSE85632.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE85632

Article and author information

Author details

Youjia Guo

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Tomohiro Kitano

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Kimiko Inoue

Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan

Competing interests
The authors declare that no competing interests exist.
Kensaku Murano

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Michiko Hirose

Bioresource Engineering Division, RIKEN BioResource Research Center, Ibaraki, Japan

Competing interests
The authors declare that no competing interests exist.
Ten D Li

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Akihiko Sakashita

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Hirotsugu Ishizu

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Narumi Ogonuki

Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan

Competing interests
The authors declare that no competing interests exist.
Shogo Matoba

Bioresource Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan

Competing interests
The authors declare that no competing interests exist.
Masayuki Sato

Department of Molecular Biology, Keio University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5484-4597
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.

"This ORCID iD identifies the author of this article:" 0000-0003-0447-1988
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.

"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.

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).

Copyright

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.