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
Further reading
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Stem cell self-renewal often relies on asymmetric fate determination governed by niche signals and/or cell-intrinsic factors but how these regulatory mechanisms cooperate to promote asymmetric fate decision remains poorly understood. In adult Drosophila midgut, asymmetric Notch (N) signaling inhibits intestinal stem cell (ISC) self-renewal by promoting ISC differentiation into enteroblast (EB). We have previously shown that epithelium-derived Bone Morphogenetic Protein (BMP) promotes ISC self-renewal by antagonizing N pathway activity (Tian and Jiang, 2014). Here, we show that loss of BMP signaling results in ectopic N pathway activity even when the N ligand Delta (Dl) is depleted, and that the N inhibitor Numb acts in parallel with BMP signaling to ensure a robust ISC self-renewal program. Although Numb is asymmetrically segregated in about 80% of dividing ISCs, its activity is largely dispensable for ISC fate determination under normal homeostasis. However, Numb becomes crucial for ISC self-renewal when BMP signaling is compromised. Whereas neither Mad RNA interference nor its hypomorphic mutation led to ISC loss, inactivation of Numb in these backgrounds resulted in stem cell loss due to precocious ISC-to-EB differentiation. Furthermore, we find that numb mutations resulted in stem cell loss during midgut regeneration in response to epithelial damage that causes fluctuation in BMP pathway activity, suggesting that the asymmetrical segregation of Numb into the future ISC may provide a fail-save mechanism for ISC self-renewal by offsetting BMP pathway fluctuation, which is important for ISC maintenance in regenerative guts.
