In mammals, the conserved telomere binding protein Rap1 serves a diverse set of nontelomeric functions, including activation of the NF-kB signaling pathway, maintenance of metabolic function in vivo, and transcriptional regulation. Here, we uncover the mechanism by which Rap1 modulates gene expression. Using a separation-of-function allele, we show that Rap1 transcriptional regulation is largely independent of TRF2-mediated binding to telomeres and does not involve direct binding to genomic loci. Instead, Rap1 interacts with the TIP60/p400 complex and modulates its histone acetyltransferase activity. Notably, we show that deletion of Rap1 in mouse embryonic stem cells increases the fraction of two-cell-like cells. Specifically, Rap1 enhances the repressive activity of Tip60/p400 across a subset of two-cell-stage genes, including Zscan4 and the endogenous retrovirus MERVL. Preferential up-regulation of genes proximal to MERVL elements in Rap1-deficient settings implicates these endogenous retroviral elements in the derepression of proximal genes. Altogether, our study reveals an unprecedented link between Rap1 and the TIP60/p400 complex in the regulation of pluripotency.

中文翻译：

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Rap1 在双细胞样状态和多能状态之间的命运转变过程中调节 TIP60 功能

在哺乳动物中，保守的端粒结合蛋白 Rap1 具有多种非端粒功能，包括激活 NF-kB 信号通路、维持体内代谢功能和转录调节。在这里，我们揭示了 Rap1 调节基因表达的机制。使用功能分离等位基因，我们表明 Rap1 转录调控在很大程度上独立于 TRF2 介导的与端粒的结合，并且不涉及与基因组基因座的直接结合。相反，Rap1 与 TIP60/p400 复合物相互作用并调节其组蛋白乙酰转移酶活性。值得注意的是，我们发现小鼠胚胎干细胞中 Rap1 的缺失会增加二细胞样细胞的比例。具体来说，Rap1 增强了 Tip60/p400 对两个细胞阶段基因子集的抑制活性，包括Zscan4和内源性逆转录病毒 MERVL。在 Rap1 缺陷环境中，靠近 MERVL 元件的基因优先上调表明这些内源性逆转录病毒元件与近端基因的抑制有关。总而言之，我们的研究揭示了 Rap1 和 TIP60/p400 复合物在多能性调控中的前所未有的联系。