Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA498305 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8106020.fastq.gz | Fastqsanger.gz | |||
| SRR8106021.fastq.gz | Fastqsanger.gz | |||
| SRR8106022.fastq.gz | Fastqsanger.gz | |||
| SRR8106023.fastq.gz | Fastqsanger.gz | |||
| SRR8106014.fastq.gz | Fastqsanger.gz |
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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
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) 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.
| S-EPMC6545155 | biostudies-literature
Project description:The molecular regulation of zygotic genome activation (ZGA) in mammals remains poorly understood. Primed mouse embryonic stem cells contain a rare subset of “2C-like” cells that are epigenetically and transcriptionally similar to the two cell embryo and thus represent an ideal system for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed exclusively in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA either in a Dux dependent or independent manner. Here we performed a candidate-based overexpression screen, identifying, amongst others, Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) as positive regulators of 2C-like cells and ZGA transcription. In the germ line, promoter DNA demethylation coincides with upregulation of Dppa2 and Dppa4 which remain expressed until E7.5 when their promoters are remethylated. Furthermore, Dppa2 and Dppa4 are also expressed during iPSC reprogramming at the time 2C-like ZGA transcription transiently peaks. Through a combination of overexpression, knockdown, knockout and rescue experiments, together with transcriptional analyses, we show that Dppa2 and Dppa4 directly regulate the 2C-like cell population and associated transcripts, including Dux and the Zscan4 cluster. Importantly, we tease apart the molecular hierarchy in which the 2C-like transcriptional program is initiated and stabilised. Dppa2 and Dppa4 require Dux to initiate 2C-like ZGA transcription, suggesting they act upstream by directly regulating Dux. Supporting this, ChIP-seq analysis revealed Dppa2 and Dppa4 bind to the Dux promoter and gene body and drive its expression. Zscan4c is also able to induce 2C-like cells in wild type cells, but, in contrast to Dux, can no longer do so in Dppa2/4 double knockout cells, suggesting it may act to stabilise rather than drive the transcriptional network. Our findings suggest a model in which Dppa2/4 binding to the Dux promoter leads to Dux upregulation and activation of the 2C-like transcriptional program which is subsequently reinforced by Zscan4c.
2018-11-29 | GSE120951 | GEO
Project description:The molecular regulation of zygotic genome activation (ZGA) in mammals remains poorly understood. Primed mouse embryonic stem cells contain a rare subset of “2C-like” cells that are epigenetically and transcriptionally similar to the two cell embryo and thus represent an ideal system for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed exclusively in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA either in a Dux dependent or independent manner. Here we performed a candidate-based overexpression screen, identifying, amongst others, Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) as positive regulators of 2C-like cells and ZGA transcription. In the germ line, promoter DNA demethylation coincides with upregulation of Dppa2 and Dppa4 which remain expressed until E7.5 when their promoters are remethylated. Furthermore, Dppa2 and Dppa4 are also expressed during iPSC reprogramming at the time 2C-like ZGA transcription transiently peaks. Through a combination of overexpression, knockdown, knockout and rescue experiments, together with transcriptional analyses, we show that Dppa2 and Dppa4 directly regulate the 2C-like cell population and associated transcripts, including Dux and the Zscan4 cluster. Importantly, we tease apart the molecular hierarchy in which the 2C-like transcriptional program is initiated and stabilised. Dppa2 and Dppa4 require Dux to initiate 2C-like ZGA transcription, suggesting they act upstream by directly regulating Dux. Supporting this, ChIP-seq analysis revealed Dppa2 and Dppa4 bind to the Dux promoter and gene body and drive its expression. Zscan4c is also able to induce 2C-like cells in wild type cells, but, in contrast to Dux, can no longer do so in Dppa2/4 double knockout cells, suggesting it may act to stabilise rather than drive the transcriptional network. Our findings suggest a model in which Dppa2/4 binding to the Dux promoter leads to Dux upregulation and activation of the 2C-like transcriptional program which is subsequently reinforced by Zscan4c.
2018-11-29 | GSE120952 | GEO
Project description:The molecular regulation of zygotic genome activation (ZGA) in mammals remains poorly understood. Primed mouse embryonic stem cells contain a rare subset of “2C-like” cells that are epigenetically and transcriptionally similar to the two cell embryo and thus represent an ideal system for studying ZGA transcription regulation. Recently, the transcription factor Dux, expressed exclusively in the minor wave of ZGA, was described to activate many downstream ZGA transcripts. However, it remains unknown what upstream maternal factors initiate ZGA either in a Dux dependent or independent manner. Here we performed a candidate-based overexpression screen, identifying, amongst others, Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) as positive regulators of 2C-like cells and ZGA transcription. In the germ line, promoter DNA demethylation coincides with upregulation of Dppa2 and Dppa4 which remain expressed until E7.5 when their promoters are remethylated. Furthermore, Dppa2 and Dppa4 are also expressed during iPSC reprogramming at the time 2C-like ZGA transcription transiently peaks. Through a combination of overexpression, knockdown, knockout and rescue experiments, together with transcriptional analyses, we show that Dppa2 and Dppa4 directly regulate the 2C-like cell population and associated transcripts, including Dux and the Zscan4 cluster. Importantly, we tease apart the molecular hierarchy in which the 2C-like transcriptional program is initiated and stabilised. Dppa2 and Dppa4 require Dux to initiate 2C-like ZGA transcription, suggesting they act upstream by directly regulating Dux. Supporting this, ChIP-seq analysis revealed Dppa2 and Dppa4 bind to the Dux promoter and gene body and drive its expression. Zscan4c is also able to induce 2C-like cells in wild type cells, but, in contrast to Dux, can no longer do so in Dppa2/4 double knockout cells, suggesting it may act to stabilise rather than drive the transcriptional network. Our findings suggest a model in which Dppa2/4 binding to the Dux promoter leads to Dux upregulation and activation of the 2C-like transcriptional program which is subsequently reinforced by Zscan4c.
2018-11-29 | GSE120950 | GEO
Project description:Obox4 secures zygotic genome activation upon loss of Dux
| PRJNA806787 | ENA
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.
2021-03-04 | GSE142043 | GEO
Project description:Dppa2 and Dppa4 directly regulate the Dux driven zygotic transcriptional program
| PRJNA495353 | ENA
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
Project description:The molecular mechanism controlling the zygotic genome activation (ZGA) in mammals remains poorly understood. The 2C-like cells spontaneously emerging from cultures of mouse embryonic stem cells (ESCs) share some key transcriptional and epigenetic programs with 2-cell stage embryos. By studying the transition of ESCs into 2C-like cells, we identified Dppa2/4 as important regulators controlling zygotic transcriptional program through directly upregulating the expression of Dux. In addition, we found that DPPA2 protein is sumoylated and its activity is negatively regulated by Sumo E3 ligase PIAS4. PIAS4 is downregulated during zygotic genome activation process and during transitioning of ESCs into 2C-like cells. Depleting Pias4 or overexpressing Dppa2/4 is sufficient to upregulateactivate 2C-like transcriptional program, while depleting Dppa2/4 or forced expression of PIAS4 or Sumo2-Dppa2 inhibits 2C-like transcriptional program. Furthermore, ectopic expression of Pias4 or Sumo2-Dppa2 impairs early mouse embryo development. In summary, our study identifies key molecular rivals consisting of transcription factors and a Sumo2 E3 ligase that regulate the transition of ESCs into 2C-like cells and zygotic transcriptional program upstream of Dux.
2019-03-06 | PXD012925 | Pride