The Yes-associated protein YAP, one of the major effectors of the Hippo pathway together with its related protein TAZ, mediates a range of cellular processes from proliferation and death to morphogenesis. YAP and TAZ regulate a large number of target genes, acting as co-activators of DNA-binding transcription factors or as negative regulators of transcription by interacting with the nucleosome remodeling and histone deacetylase complexes. YAP is expressed in self-renewing embryonic stem cells (ESCs), although it is still debated whether it plays any crucial roles in the control of either stemness or differentiation. Here we show that the transient downregulation of YAP in mouse ESCs perturbs cellular homeostasis, leading to the inability to differentiate properly. Bisulfite genomic sequencing revealed that this transient knockdown caused a genome-wide alteration of the DNA methylation remodeling that takes place during the early steps of differentiation, suggesting that the phenotype we observed might be due to the dysregulation of some of the mechanisms involved in regulation of ESC exit from pluripotency. By gene expression analysis we identified two molecules which could have a role in the altered genome-wide methylation profile: the long non-coding RNA Ephemeron, whose rapid upregulation is crucial for ESCs transition into epiblast, and the methyltransferase-like protein Dnmt3l, which, during the embryo development, cooperates with Dnmt3a and Dnmt3b to contribute to the de novo DNA methylation that governs early steps of ESC differentiation. These data suggest a new role for YAP in the governance of the epigenetic dynamics of exit from pluripotency.

中文翻译：

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YAP 有助于小鼠胚胎干细胞分化的 DNA 甲基化重塑

Yes 相关蛋白 YAP 是 Hippo 通路的主要效应物之一，与其相关蛋白 TAZ 一起介导从增殖和死亡到形态发生的一系列细胞过程。YAP 和 TAZ 调节大量靶基因，通过与核小体重塑和组蛋白脱乙酰酶复合物相互作用，作为 DNA 结合转录因子的共激活剂或作为转录的负调节剂。YAP 在自我更新的胚胎干细胞 (ESC) 中表达，尽管它是否在控制干细胞或分化方面发挥任何关键作用仍存在争议。在这里，我们表明小鼠 ESC 中 YAP 的瞬时下调扰乱了细胞稳态，导致无法正确分化。亚硫酸氢盐基因组测序显示，这种瞬时敲低导致了在分化早期阶段发生的 DNA 甲基化重塑的全基因组改变，这表明我们观察到的表型可能是由于参与调控的一些机制失调所致。 ESC退出多能性。通过基因表达分析，我们确定了两种可能在改变的全基因组甲基化谱中起作用的分子：长链非编码 RNA Ephemeron，其快速上调对 ESC 转化为外胚层至关重要，以及甲基转移酶样蛋白 Dnmt3l，其在胚胎发育过程中，与 Dnmt3a 和 Dnmt3b 合作，促进控制 ESC 分化早期步骤的从头 DNA 甲基化。