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Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice III

ABSTRACT: In mammalian embryos, Dux transcription factors (TF) drive a cleavage stage-specific transcriptional burst associated with zygotic genome activation (ZGA) during which hundreds of genes and endogenous retroviral (ERV) elements are transiently expressed. In mice, ZGA begins in late 1-cell (1C) embryos and is shut down within hours at the late 2-cell (2C) to 4-cell (4C) stage. While this transition is accompanied by the loss of totipotency, it is not clear whether shutdown of Dux-induced ZGA is required for this process and how ZGA is terminated. Here, we reveal an essential negative feedback axis by which the Dux family member Duxbl terminates Dux-induced ZGA from the mid 2C stage onward by direct suppression of genomic Dux target loci. Consequently, Duxbl inactivation results in sustained expression of Dux-induced ZGA leading to 4C arrest. Our study reveals the Dux/Duxbl axis that determines the timing of totipotency exit enabling the very first divergence of cell fates.

ORGANISM(S): Mus musculus

PROVIDER: GSE213702 | GEO | 2023/12/07

REPOSITORIES: GEO

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Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice II

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Duxbl-mediated suppression of ZGA drives totipotency to pluripotency transition in mice I

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The homeobox transcription factor DUXBL controls exit from totipotency

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

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2019-04-10 | GSE121746 | GEO

DPPA2 and DPPA4 are necessary to establish a 2C-like state in mouse embryonic stem cells [ChIP-seq]

Project description:After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through so-called zygotic genome activation (ZGA), occurring in the mouse at the 2-cell (2C) stage. Amongst the first elements to be transcribed are the Dux gene, the product of which secondarily induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons, which regulate chromatin accessibility in the early embryo. The maternally-inherited factors that activate Dux and LINE-1 transcription have so far remained unknown. Mouse embryonic stem cells (mESCs) recapitulate some aspects of ZGA in culture, owing to their ability to cycle through a 2C-like stage where Dux, its target genes and LINE-1 integrants are expressed. Here we identify the paralog proteins DPPA2 and DPPA4 as necessary for activation of Dux and LINE-1 expression in mESCs. Since their encoding RNAs are maternally transmitted to the zygote, it is likely that these factors are important upstream mediators of murine ZGA.

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DPPA2 and DPPA4 are necessary to establish a 2C-like state in mouse embryonic stem cells [RNA-seq]

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DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate the emergence of 2C-like cells and zygotic transcriptional program

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

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