Long Noncoding RNA-1604 Orchestrates Neural Differentiation through the miR-200c/ZEB Axis
Long Noncoding RNA-1604 Orchestrates Neural Differentiation through the miR-200c/ZEB Axis
复制标题
长非编码 RNA-1604 通过 miR-200c/ZEB 轴协调神经分化
DOI：
10.1002/stem.2749
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发表时间：
2018-03-01
期刊：
影响因子：
5.2
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
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作者：
Weng, Rong;Lu, Chenqi;Kang, Jiuhong
阐明胚胎干细胞（ESC）神经分化的调控机制不仅有助于理解神经发育，而且有助于获得干细胞治疗神经退行性疾病所需的高质量神经前体细胞。在此，我们发现长链非编码RNA 1604（lncRNA-1604）在神经分化过程中在细胞质中高度表达，并且lncRNA-1604的敲低在体外和体内均显著抑制小鼠ESCs的神经分化。生物信息学预测和机制分析表明，lncRNA-1604作为一种新的竞争性内源性RNA参与miR-200 c的调控，并在神经分化过程中调控核心转录因子ZEB 1和ZEB 2。此外，我们还证明了miR-200 c和ZEB 1/2在小鼠神经分化中的关键作用。无论是导入miR-200 c海绵还是过表达ZEB 1/2都显著逆转了lncRNA-1604敲除诱导的小鼠ESC神经分化抑制。总的来说，这些发现不仅确定了lncRNA-1604和ZEB 1/2以前未知的作用，而且还阐明了神经分化中新的调控lncRNA-1604/miR-200 c/ZEB轴。
Clarifying the regulatory mechanisms of embryonic stem cell (ESC) neural differentiation is helpful not only for understanding neural development but also for obtaining high-quality neural progenitor cells required by stem cell therapy of neurodegenerative diseases. Here, we found that long noncoding RNA 1604 (lncRNA-1604) was highly expressed in cytoplasm during neural differentiation, and knockdown of lncRNA-1604 significantly repressed neural differentiation of mouse ESCs both in vitro and in vivo. Bioinformatics prediction and mechanistic analysis revealed that lncRNA-1604 functioned as a novel competing endogenous RNA of miR-200c and regulated the core transcription factors ZEB1 and ZEB2 during neural differentiation. Furthermore, we also demonstrated the critical role of miR-200c and ZEB1/2 in mouse neural differentiation. Either introduction of miR-200c sponge or overexpression of ZEB1/2 significantly reversed the lncRNA-1604 knockdown-induced repression of mouse ESC neural differentiation. Collectively, these findings not only identified a previously unknown role of lncRNA-1604 and ZEB1/2 but also elucidated a new regulatory lncRNA-1604/miR-200c/ZEB axis in neural differentiation.