The regulatory circuitry underlying embryonic stem (ES) cell self‐renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA‐binding proteins (RBPs) have essential roles in RNA‐mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified seven RBPs played important roles for the exit from pluripotency of ES cells. We characterized hnRNPLL, which mainly functions as a global regulator of alternative splicing in ES cells. Specifically, hnRNPLL promotes multiple ES cell‐preferred exon skipping events during the onset of ES cell differentiation. hnRNPLL depletion thus leads to sustained expression of ES cell‐preferred isoforms, resulting in a differentiation deficiency that causes developmental defects and growth impairment in hnRNPLL‐KO mice. In particular, hnRNPLL‐mediated alternative splicing of two transcription factors, Bptf and Tbx3, is important for pluripotency exit. These data uncover the critical role of RBPs in pluripotency exit and suggest the application of targeting RBPs in controlling ES cell fate.

中文翻译：

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hnRNPLL 通过调节 Tbx3 和 Bptf 的选择性剪接来控制胚胎干细胞的多能性退出


胚胎干（ES）细胞自我更新的调节回路已被明确定义，但如何分解该回路以实现谱系规范尚不清楚。 RNA 结合蛋白 (RBP) 在 RNA 介导的基因调控中发挥重要作用，初步数据表明它们可能调控 ES 细胞的命运。通过将生物信息分析与功能筛选相结合，我们确定了七个 RBP 在 ES 细胞退出多能性方面发挥着重要作用。我们对 hnRNPLL 进行了表征，它主要作为 ES 细胞中选择性剪接的全局调节器。具体来说，hnRNPLL 在 ES 细胞分化开始期间促进多个 ES 细胞偏好的外显子跳跃事件。因此，hnRNPLL 耗竭导致 ES 细胞首选亚型的持续表达，导致分化缺陷，导致hnRNPLL ‐KO 小鼠发育缺陷和生长障碍。特别是，hnRNPLL 介导的两个转录因子Bptf和Tbx3的选择性剪接对于多能性的退出非常重要。这些数据揭示了 RBP 在多能性退出中的关键作用，并表明靶向 RBP 在控制 ES 细胞命运中的应用。