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
-
- 1,271
- views
-
- 226
- downloads
-
- 6
- 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
The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic regions, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.
-
- Developmental Biology
Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2-specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Overexpression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.
