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.
-
Obox4 secures zygotic genome activation upon loss of DuxNCBI Gene Expression Omnibus, GSE196671.
-
Single-cell RNA-Seq reveals dynamic, random monoallelic gene expression in mammalian cellsNCBI Gene Expression Omnibus, GSE45719.
-
Mouse totipotent stem cells captured and maintained through spliceosomal repressionNCBI Gene Expression Omnibus, GSE168728.
-
Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse developmentNCBI Gene Expression Omnibus, GSE121746.
-
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.
Metrics
-
- 1,405
- views
-
- 240
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Obox4 promotes zygotic genome activation upon loss of Dux
eLife 13:e95856.
https://doi.org/10.7554/eLife.95856
Further reading
-
- Developmental Biology
Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.
-
- Computational and Systems Biology
- Developmental Biology
The Notch signaling pathway uses families of ligands and receptors to transmit signals to nearby cells. These components are expressed in diverse combinations in different cell types, interact in a many-to-many fashion, both within the same cell (in cis) and between cells (in trans), and their interactions are modulated by Fringe glycosyltransferases. A fundamental question is how the strength of Notch signaling depends on which pathway components are expressed, at what levels, and in which cells. Here, we used a quantitative, bottom-up, cell-based approach to systematically characterize trans-activation, cis-inhibition, and cis-activation signaling efficiencies across a range of ligand and Fringe expression levels in Chinese hamster and mouse cell lines. Each ligand (Dll1, Dll4, Jag1, and Jag2) and receptor variant (Notch1 and Notch2) analyzed here exhibited a unique profile of interactions, Fringe dependence, and signaling outcomes. All four ligands were able to bind receptors in cis and in trans, and all ligands trans-activated both receptors, although Jag1-Notch1 signaling was substantially weaker than other ligand-receptor combinations. Cis-interactions were predominantly inhibitory, with the exception of the Dll1- and Dll4-Notch2 pairs, which exhibited cis-activation stronger than trans-activation. Lfng strengthened Delta-mediated trans-activation and weakened Jagged-mediated trans-activation for both receptors. Finally, cis-ligands showed diverse cis-inhibition strengths, which depended on the identity of the trans-ligand as well as the receptor. The map of receptor-ligand-Fringe interaction outcomes revealed here should help guide rational perturbation and control of the Notch pathway.
