A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation

During implantation, embryos undergo an unpolarized-to-polarized transition to initiate postimplantation morphogenesis. However, the underlying molecular mechanism is unknown. Here, we identify a transient transcriptional activation governing embryonic morphogenesis and pluripotency transition during implantation. In naive pluripotent embryonic stem cells (ESCs), which represent preimplantation embryos, we find that the microprocessor component DGCR8 can recognize stem-loop structures within nascent mRNAs to sequester transcriptional coactivator FLII to suppress transcription directly. When mESCs exit from naive pluripotency, the ERK/RSK/P70S6K pathway rapidly activates, leading to FLII phosphorylation and disruption of DGCR8/FLII interaction. Phosphorylated FLII can bind to transcription factor JUN, activating cell migration-related genes to establish poised pluripotency akin to implanting embryos. Resequestration of FLII by DGCR8 drives poised ESCs into formative pluripotency. In summary, we identify a DGCR8/FLII/JUN-mediated transient transcriptional activation mechanism. Disruption of this mechanism inhibits naive-poised-formative pluripotency transition and the corresponding unpolarized-to-polarized transition during embryo implantation, which are conserved in mice and humans. [Display omitted] •DGCR8 binds to nascent mRNAs, inhibiting their transcription by sequestering FLII•Phosphorylated FLII, induced by the ERK pathway, dissociates from DGCR8 and binds to JUN•FLII facilitates JUN in activating gene expression related to cell migration•The interplay a DGCR8/FLII/JUN governs morphogenesis of implanting embryos Lyu et al. discover that DGCR8 acts as a transcriptional repressor by binding to target nascent RNAs and sequestering FLII. During implantation, ERK-induced FLII phosphorylation enables dissociation of the DGCR8/FLII complex and formation of the FLII/JUN complex, transiently activating cell migration genes to promote morphogenesis and establish poised pluripotency in implanting embryos.