The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5 signalling and ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern 2C gene transcription and a key mESC rejuvenation process.

中文翻译：

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ERK5-KLF2 信号模块调节干细胞中的早期胚胎基因表达和端粒再生

ERK5 MAP 激酶信号通路驱动小鼠胚胎干细胞 (mESC) 中幼稚多能性基因的转录。然而，尚未研究 ERK5 如何影响 mESC 生物学的其他方面。在这里，我们采用定量蛋白质组学分析来鉴定其表达受 mESC 中 ERK5 通路调节的蛋白质。这揭示了 ERK5 信号在调节动态表达的早期胚胎 2 细胞阶段 (2C) 基因（包括 mESC 返老还童因子 ZSCAN4）中的功能。mESC 中的 ERK5 信号传导和 ZSCAN4 诱导增加了端粒长度，这是延长培养所需的关键恢复过程。从机制上讲，ERK5 通过 KLF2 多能性转录因子的转录促进 ZSCAN4 和 2C 基因表达。出奇，ERK5 还直接磷酸化 KLF2 以驱动泛素依赖性降解，编码 2C 基因表达的负反馈调节。总之，我们的数据确定了一个调节模块，通过该模块 ERK5 激酶和转录活动双向控制 KLF2 水平以模式 2C 基因转录和关键的 mESC 复兴过程。