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A DGCR8/FLII-dominated on-off switch for immediate-early genes governs embryo implantation in mouse and human [eCLIP]

ABSTRACT: As an essential checkpoint for successful pregnancy, mammalian embryo implantation initiates fetal-maternal communication. However, the underlying transcriptional regulation governing such a fast transition is still unknown. Here, we identify a DGCR8/FLII-dominated on-off switch for immediate-early genes (IEGs) governing pluripotency transition and morphogenesis of epiblasts upon embryo implantation. In mouse naïve embryonic stem cells (mESCs), we find the Microprocessor component DGCR8, but not DROSHA, can recognize mRNA stem-loop structures and further interact with and occupy transcriptional activator FLII to directly suppress transcription of non-miRNA target genes. Interestingly, when mESCs exit from naïve pluripotency, ERK signaling is quickly activated to induce FLII phosphorylation and disrupt DGCR8/FLII interaction. Phosphorylated FLII then binds to AP1, a typical IEG, to mediate the transcriptional activation of cell migration-related genes to establish poised pluripotency. Re-occupation of FLII by DGCR8 drives poised ESCs into formative pluripotency. Disruption of the DGCR8/FLII-mediated transcriptional activation inhibits the naïve-poised-formative ESC transition and the corresponding embryonic morphogenesis during implanting period, which is conserved in mouse and human.

ORGANISM(S): Mus musculus

PROVIDER: GSE256240 | GEO | 2024/07/08

REPOSITORIES: GEO

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Project description:As an essential checkpoint for successful pregnancy, mammalian embryo implantation initiates fetal-maternal communication. However, the underlying transcriptional regulation governing such a fast transition is still unknown. Here, we identify a DGCR8/FLII-dominated on-off switch for immediate-early genes (IEGs) governing pluripotency transition and morphogenesis of epiblasts upon embryo implantation. In mouse naïve embryonic stem cells (mESCs), we find the Microprocessor component DGCR8, but not DROSHA, can recognize mRNA stem-loop structures and further interact with and occupy transcriptional activator FLII to directly suppress transcription of non-miRNA target genes. Interestingly, when mESCs exit from naïve pluripotency, ERK signaling is quickly activated to induce FLII phosphorylation and disrupt DGCR8/FLII interaction. Phosphorylated FLII then binds to AP1, a typical IEG, to mediate the transcriptional activation of cell migration-related genes to establish poised pluripotency. Re-occupation of FLII by DGCR8 drives poised ESCs into formative pluripotency. Disruption of the DGCR8/FLII-mediated transcriptional activation inhibits the naïve-poised-formative ESC transition and the corresponding embryonic morphogenesis during implanting period, which is conserved in mouse and human.

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