Obox4 promotes zygotic genome activation upon loss of Dux
- Keio University, Japan
- RIKEN BioResource Research Center, Japan
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.
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Obox4 secures zygotic genome activation upon loss of DuxNCBI Gene Expression Omnibus, GSE196671.
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Single-cell RNA-Seq reveals dynamic, random monoallelic gene expression in mammalian cellsNCBI Gene Expression Omnibus, GSE45719.
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Mouse totipotent stem cells captured and maintained through spliceosomal repressionNCBI Gene Expression Omnibus, GSE168728.
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Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse developmentNCBI Gene Expression Omnibus, GSE121746.
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RNAseq of DUX KO mouse 2-cell embryosNCBI Gene Expression Omnibus, GSE141321.
Article and author information
Author details
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
© 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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Obox4 promotes zygotic genome activation upon loss of Dux
eLife 13:e95856.
https://doi.org/10.7554/eLife.95856
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During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory toward the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.
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