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Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development.

ABSTRACT: How maternal factors in oocytes trigger zygotic genome activation (ZGA) is a long-standing question in developmental biology. Recent studies in 2-cell-like embryonic stem cells (2C-like cells) suggest that transcription factors of the DUX family are key regulators of ZGA in placental mammals1,2. To characterize the role of DUX in ZGA, we generated Dux cluster knockout (KO) mouse lines. Unexpectedly, we found that both Dux zygotic KO (Z-KO) and maternal and zygotic KO (MZ-KO) embryos can survive to adulthood despite showing reduced developmental potential. Furthermore, transcriptome profiling of the MZ-KO embryos revealed that loss of DUX has minimal effects on ZGA and most DUX targets in 2C-like cells are normally activated in MZ-KO embryos. Thus, contrary to the key function of DUX in inducing 2C-like cells, our data indicate that DUX has only a minor role in ZGA and that loss of DUX is compatible with mouse development.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6545155 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development.

Chen Zhiyuan Z Zhang Yi Y

Nature genetics 20190527 6

How maternal factors in oocytes trigger zygotic genome activation (ZGA) is a long-standing question in developmental biology. Recent studies in 2-cell-like embryonic stem cells (2C-like cells) suggest that transcription factors of the DUX family are key regulators of ZGA in placental mammals<sup>1,2</sup>. To characterize the role of DUX in ZGA, we generated Dux cluster knockout (KO) mouse lines. Unexpectedly, we found that both Dux zygotic KO (Z-KO) and maternal and zygotic KO (MZ-KO) embryos c ...[more]

PMID: 31133747

Similar Datasets

Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development

Project description:How maternal factors in oocytes trigger zygotic genome activation (ZGA) is a long-standing question in developmental biology. Recent studies in 2-cell like embryonic stem cells (2C-like cells) implicate that the DUX family transcription factors are key regulators of ZGA in placental mammals. To characterize the role of DUX in ZGA, we generated Dux cluster knockout (KO) mouse lines. Unexpectedly, we found both Dux zygotic KO (Z-KO) and maternal/zygotic KO (MZ-KO) embryos can survive to adulthood despite showing reduced developmental potential. Furthermore, transcriptome profiling of the MZ-KO embryos revealed that loss of DUX has minimal effect on ZGA and most DUX targets in 2C-like cells are normally activated in MZ-KO embryos. Thus, contrary to the key function in inducing 2C-like cells, our data indicate that DUX only has a minor role in ZGA and loss of DUX is compatible with mouse development.

2019-04-10 | GSE121746 | GEO

Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development

Project description:Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development

| PRJNA498305 | ENA

Minor zygotic gene activation is essential for mouse preimplantation development.

Project description:In mice, transcription initiates at the mid-one-cell stage and transcriptional activity dramatically increases during the two-cell stage, a process called zygotic gene activation (ZGA). Associated with ZGA is a marked change in the pattern of gene expression that occurs after the second round of DNA replication. To distinguish ZGA before and after the second-round DNA replication, the former and latter are called minor and major ZGA, respectively. Although major ZGA are required for development beyond the two-cell stage, the function of minor ZGA is not well understood. Transiently inhibiting minor ZGA with 5, 6-dichloro-1-?-d-ribofuranosyl-benzimidazole (DRB) resulted in the majority of embryos arresting at the two-cell stage and retention of the H3K4me3 mark that normally decreases. After release from DRB, at which time major ZGA normally occurred, transcription initiated with characteristics of minor ZGA but not major ZGA, although degradation of maternal mRNA normally occurred. Thus, ZGA occurs sequentially starting with minor ZGA that is critical for the maternal-to-zygotic transition.

| S-EPMC6055165 | biostudies-literature

Dux facilitates post-implantation development, but is not essential for zygotic genome activation†.

Project description:Double homeobox genes are unique to eutherian mammals. It has been proposed that the DUXC clade of the double homeobox gene family, which is present in multicopy long tandem arrays, plays an essential role in zygotic genome activation (ZGA). We generated a deletion of the tandem array encoding the DUXC gene of mouse, Double homeobox (Dux), and found it surprisingly to be homozygous viable and fertile. We characterize the embryonic development and ZGA profile of knockout (KO) embryos, finding that zygotic genome activation still occurs, with only modest alterations in 2-cell embryo gene expression, no defect in in vivo preimplantation development, but an increased likelihood of post-implantation developmental failure, leading to correspondingly smaller litter sizes in the KO strain. While all known 2-cell specific Dux target genes are still expressed in the KO, a subset is expressed at lower levels. These include numerous genes involved in methylation, blastocyst development, and trophectoderm/placental development. We propose that rather than driving ZGA, which is a process common throughout the animal kingdom, DUXC genes facilitate a process unique to eutherian mammals, namely the post-implantation development enabled by an invasive placenta.

| S-EPMC7786258 | biostudies-literature

Paternal H3K4 methylation is required for minor zygotic gene activation and early mouse embryonic development.

Project description:Epigenetic modifications, such as DNA methylation and histone modifications, are dynamically altered predominantly in paternal pronuclei soon after fertilization. To identify which histone modifications are required for early embryonic development, we utilized histone K-M mutants, which prevent endogenous histone methylation at the mutated site. We prepared four single K-M mutants for histone H3.3, K4M, K9M, K27M, and K36M, and demonstrate that overexpression of H3.3 K4M in embryos before fertilization results in developmental arrest, whereas overexpression after fertilization does not affect the development. Furthermore, loss of H3K4 methylation decreases the level of minor zygotic gene activation (ZGA) predominantly in the paternal pronucleus, and we obtained similar results from knockdown of the H3K4 methyltransferase Mll3/4. We therefore conclude that H3K4 methylation, likely established by Mll3/4 at the early pronuclear stage, is essential for the onset of minor ZGA in the paternal pronucleus, which is necessary for subsequent preimplantation development in mice.

| S-EPMC4515120 | biostudies-literature

Loss of Axin2 Causes Ocular Defects During Mouse Eye Development.

Project description:PurposeThe scaffold protein Axin2 is an antagonist and universal target of the Wnt/?-catenin pathway. Disruption of Axin2 may lead to developmental eye defects; however, this has not been examined. The purpose of this study was to investigate the role of Axin2 during ocular and extraocular development in mouse.MethodsAnimals heterozygous and homozygous for a Axin2lacZ knock-in allele were analyzed at different developmental stages for reporter expression, morphology as well as for the presence of ocular and extraocular markers using histologic and immunohistochemical techniques.ResultsDuring early eye development, the Axin2lacZ reporter was expressed in the periocular mesenchyme, RPE, and optic stalk. In the developing retina, Axin2lacZ reporter expression was initiated in ganglion cells at late embryonic stages and robustly expressed in subpopulations of amacrine and horizontal cells postnatally. Activation of the Axin2lacZ reporter overlapped with labeling of POU4F1, PAX6, and Calbindin. Germline deletion of Axin2 led to variable ocular phenotypes ranging from normal to severely defective eyes exhibiting microphthalmia, coloboma, lens defects, and expanded ciliary margin. These defects were correlated with abnormal tissue patterning in individual affected tissues, such as the optic fissure margins in the ventral optic cup and in the expanded ciliary margin.ConclusionsOur results reveal a critical role for Axin2 during ocular development, likely by restricting the activity of the Wnt/?-catenin pathway.

| S-EPMC5054732 | biostudies-literature

DUX is a non-essential synchronizer of zygotic genome activation.

Project description:Some of the earliest transcripts produced in fertilized human and mouse oocytes code for DUX, a double homeodomain protein that promotes embryonic genome activation (EGA). Deleting Dux by genome editing at the one- to two-cell stage in the mouse impairs EGA and blastocyst maturation. Here, we demonstrate that mice carrying homozygous Dux deletions display markedly reduced expression of DUX target genes and defects in both pre- and post-implantation development, with, notably, a disruption of the pace of the first few cell divisions and significant rates of late embryonic mortality. However, some Dux -/- embryos give rise to viable pups, indicating that DUX is important but not strictly essential for embryogenesis.

| S-EPMC7099940 | biostudies-literature

DUX-family transcription factors regulate zygotic genome activation in placental mammals.

Project description:In animal embryos, transcription is mostly silent for several cell divisions, until the release of the first major wave of embryonic transcripts through so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio, but their mammalian homologs are still undefined. Here, we provide evidence that the DUX family of transcription factors is essential to this process in mice and potentially in humans. First, human DUX4 and mouse Dux are both expressed before ZGA in their respective species. Second, both orthologous proteins bind the promoters of ZGA-associated genes and activate their transcription. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents the cells from cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA. We conclude that DUX-family proteins are key inducers of zygotic genome activation in placental mammals.

| S-EPMC5446900 | biostudies-literature

Obox4 secures zygotic genome activation upon loss of Dux

Project description:We report that the multicopy mouse homeobox gene Obox4 encodes a transcription factor that redundantly drives ZGA. OBOX4 is highly expressed in mouse 2-cell embryos. Obox4 or Dux single knockdown is tolerated by embryogenesis, whereas Obox4/Dux double knockdown completely compromises embryonic development. Genome-wide epigenetic profiling reveals that OBOX4 binds MERVL LTRs and murine endogenous retrovirus with lysine tRNA primer (MERVK) LTRs and mediates deposition of active histone modifications.

2023-08-29 | GSE196671 | GEO

Symmetrically dimethylated histone H3R2 promotes global transcription during minor zygotic genome activation in mouse pronuclei.

Project description:Paternal genome reprogramming, such as protamine-histone exchange and global DNA demethylation, is crucial for the development of fertilised embryos. Previously, our study showed that one of histone arginine methylation, asymmetrically dimethylated histone H3R17 (H3R17me2a), is necessary for epigenetic reprogramming in the mouse paternal genome. However, roles of histone arginine methylation in reprogramming after fertilisation are still poorly understood. Here, we report that H3R2me2s promotes global transcription at the 1-cell stage, referred to as minor zygotic genome activation (ZGA). The inhibition of H3R2me2s by expressing a histone H3.3 mutant H3.3R2A prevented embryonic development from the 2-cell to 4-cell stages and significantly reduced global RNA synthesis and RNA polymerase II (Pol II) activity. Consistent with this result, the expression levels of MuERV-L as minor ZGA transcripts were decreased by forced expression of H3.3R2A. Furthermore, treatment with an inhibitor and co-injection of siRNA to PRMT5 and PRMT7 also resulted in the attenuation of transcriptional activities with reduction of H3R2me2s in the pronuclei of zygotes. Interestingly, impairment of H3K4 methylation by expression of H3.3K4M resulted in a decrease of H3R2me2s in male pronuclei. Our findings suggest that H3R2me2s together with H3K4 methylation is involved in global transcription during minor ZGA in mice.

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