Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany.
Laboratory for Developmental and Regenerative RNA biology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931, Cologne, Germany.
Nat Commun. 2017 Nov 13;8(1):1456. doi: 10.1038/s41467-017-01744-5.
While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.
虽然人类胚胎干细胞（hESC）的转录网络已经得到了广泛的研究，但对于转录后调控如何决定 hESC 功能，我们知之甚少。RNA 结合蛋白在 RNA 调控中发挥着核心作用，包括翻译和周转。在这里，我们表明 RNA 结合蛋白 CSDE1（冷休克结构域包含 E1）在 hESC 中高度表达，以维持其未分化状态并防止默认的神经命运。值得注意的是，CSDE1 的缺失会加速神经分化并增强神经发生。相反，CSDE1 的异位表达会损害神经分化。我们发现 CSDE1 在后转录水平上调节 hESC 身份、神经外胚层承诺和神经发生的多个调节节点的核心组件。在这些关键的促神经/神经元因子中，CSDE1 结合脂肪酸结合蛋白 7（FABP7）和波形蛋白（VIM）mRNA，以及参与神经元投射发育的转录本，调节它们的稳定性和翻译。因此，我们的研究结果揭示了 CSDE1 是 hESC 身份和神经发生的中央转录后调控因子。
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