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.
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Project description:Maternal-deposited factors initiate zygotic genome activation (ZGA), driving the maternal-to-zygotic transition; however, the coordination between maternal coactivators and transcription factors (TFs) in this process remains unclear. In this study, by profiling the dynamic landscape of p300 during mouse ZGA, we reveal its role in promoting RNA polymerase II (Pol II) pre-configuration at ZGA gene regions and sequentially establishing enhancer activity and regulatory networks. Moreover, p300/CBP-catalyzed acetylation drives Pol II elongation and minor ZGA gene expression by inducing pivotal TFs such as Dux. Remarkably, the supplementation of exogenous Dux rescues ZGA failure and developmental defects caused by the loss of p300/CBP acetylation. DUX functions as a pioneer factor, guiding p300 and Pol II to minor ZGA gene regions and activating them in a manner dependent on the non-catalytic functions of p300/CBP. Together, our findings reveal a mutual dependency between p300/CBP and DUX, highlighting their coordinated role in regulating minor ZGA activation.
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Project description:Maternal-deposited factors initiate zygotic genome activation (ZGA), driving the maternal-to-zygotic transition; however, the coordination between maternal coactivators and transcription factors (TFs) in this process remains unclear. In this study, by profiling the dynamic landscape of p300 during mouse ZGA, we reveal its role in promoting RNA polymerase II (Pol II) pre-configuration at ZGA gene regions and sequentially establishing enhancer activity and regulatory networks. Moreover, p300/CBP-catalyzed acetylation drives Pol II elongation and minor ZGA gene expression by inducing pivotal TFs such as Dux. Remarkably, the supplementation of exogenous Dux rescues ZGA failure and developmental defects caused by the loss of p300/CBP acetylation. DUX functions as a pioneer factor, guiding p300 and Pol II to minor ZGA gene regions and activating them in a manner dependent on the non-catalytic functions of p300/CBP. Together, our findings reveal a mutual dependency between p300/CBP and DUX, highlighting their coordinated role in regulating minor ZGA activation.
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Project description:Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition, yet the regulatory mechanisms driving minor ZGA genes remain elusive. Here we show that dynamic regulation of H3K9me2 is essential for minor ZGA. H3K9me2 levels at minor ZGA gene loci are reduced at early 2-cell and are re-established by morula. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 and impaired minor ZGA in early 2-cell, followed by developmental arrest at 2- to 4-cell. In mESCs, H3K9 at minor ZGA loci is highly di-methylated; combined loss of the H3K9 methyltransferases G9a and SETDB1 leads to synergistic de-repression of minor ZGA genes. Mechanistically, SETDB1 specifically targets Dux, while G9a broadly represses minor ZGA genes through H3K9 di-methylation linked to lamina-associated heterochromatin formation. These findings establish H3K9me2 dynamics as a key regulator for minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
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Project description:Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition, yet the regulatory mechanisms driving minor ZGA genes remain elusive. Here we show that dynamic regulation of H3K9me2 is essential for minor ZGA. H3K9me2 levels at minor ZGA gene loci are reduced at early 2-cell and are re-established by morula. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 and impaired minor ZGA in early 2-cell, followed by developmental arrest at 2- to 4-cell. In mESCs, H3K9 at minor ZGA loci is highly di-methylated; combined loss of the H3K9 methyltransferases G9a and SETDB1 leads to synergistic de-repression of minor ZGA genes. Mechanistically, SETDB1 specifically targets Dux, while G9a broadly represses minor ZGA genes through H3K9 di-methylation linked to lamina-associated heterochromatin formation. These findings establish H3K9me2 dynamics as a key regulator for minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
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Project description:Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition, yet the regulatory mechanisms driving minor ZGA genes remain elusive. Here we show that dynamic regulation of H3K9me2 is essential for minor ZGA. H3K9me2 levels at minor ZGA gene loci are reduced at early 2-cell and are re-established by morula. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 and impaired minor ZGA in early 2-cell, followed by developmental arrest at 2- to 4-cell. In mESCs, H3K9 at minor ZGA loci is highly di-methylated; combined loss of the H3K9 methyltransferases G9a and SETDB1 leads to synergistic de-repression of minor ZGA genes. Mechanistically, SETDB1 specifically targets Dux, while G9a broadly represses minor ZGA genes through H3K9 di-methylation linked to lamina-associated heterochromatin formation. These findings establish H3K9me2 dynamics as a key regulator for minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
2026-04-19 | GSE296991 | GEO
Project description:Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition, yet the regulatory mechanisms driving minor ZGA genes remain elusive. Here we show that dynamic regulation of H3K9me2 is essential for minor ZGA. H3K9me2 levels at minor ZGA gene loci are reduced at early 2-cell and are re-established by morula. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 and impaired minor ZGA in early 2-cell, followed by developmental arrest at 2- to 4-cell. In mESCs, H3K9 at minor ZGA loci is highly di-methylated; combined loss of the H3K9 methyltransferases G9a and SETDB1 leads to synergistic de-repression of minor ZGA genes. Mechanistically, SETDB1 specifically targets Dux, while G9a broadly represses minor ZGA genes through H3K9 di-methylation linked to lamina-associated heterochromatin formation. These findings establish H3K9me2 dynamics as a key regulator for minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
2026-04-19 | GSE296992 | GEO
Project description:Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition, yet the regulatory mechanisms driving minor ZGA genes remain elusive. Here we show that dynamic regulation of H3K9me2 is essential for minor ZGA. H3K9me2 levels at minor ZGA gene loci are reduced at early 2-cell and are re-established by morula. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 and impaired minor ZGA in early 2-cell, followed by developmental arrest at 2- to 4-cell. In mESCs, H3K9 at minor ZGA loci is highly di-methylated; combined loss of the H3K9 methyltransferases G9a and SETDB1 leads to synergistic de-repression of minor ZGA genes. Mechanistically, SETDB1 specifically targets Dux, while G9a broadly represses minor ZGA genes through H3K9 di-methylation linked to lamina-associated heterochromatin formation. These findings establish H3K9me2 dynamics as a key regulator for minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
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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.
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