Dormancy is a key feature of stem cell function in adult tissues as well as in embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for preimplantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in the loss of pluripotent cells. Through the integration of high-sensitivity small RNA expression profiling of individual embryos and protein expression of miRNA targets with public data of protein–protein interactions, we constructed the miRNA-mediated regulatory network of mouse early embryos specific to diapause. We find that individual miRNAs contribute to the combinatorial regulation by the network, and the perturbation of the network compromises embryo survival in diapause. We further identified the nutrient-sensitive transcription factor TFE3 as an upstream regulator of diapause-specific miRNAs, linking cytoplasmic MTOR activity to nuclear miRNA biogenesis. Our results place miRNAs as a critical regulatory layer for the molecular rewiring of early embryos to establish dormancy.

中文翻译：

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组合 microRNA 活性对于多能细胞从增殖转变为休眠至关重要


休眠是成体组织以及滞育情况下胚胎细胞干细胞功能的一个关键特征。休眠的建立是一个活跃的过程，涉及广泛的转录、表观遗传和代谢重连。这些过程如何协调以成功地将细胞转变为休眠状态仍不清楚。在这里，我们发现 microRNA 活性对于植入前发育来说是可有可无的，但对于早期小鼠胚胎适应滞育休眠状态至关重要。特别是，多能外胚层依赖于 miRNA 活性，缺乏 miRNA 活性会导致多能细胞的损失。通过将单个胚胎的高灵敏度小RNA表达谱和miRNA靶点的蛋白质表达与蛋白质-蛋白质相互作用的公共数据相结合，我们构建了miRNA介导的小鼠早期胚胎滞育特异性调控网络。我们发现单个 miRNA 有助于网络的组合调节，而网络的扰动会损害滞育中的胚胎存活。我们进一步确定了营养敏感转录因子 TFE3 作为滞育特异性 miRNA 的上游调节因子，将细胞质 MTOR 活性与核 miRNA 生物发生联系起来。我们的研究结果将 miRNA 视为早期胚胎分子重新布线以建立休眠的关键调控层。