The Nuclear Receptor Nr5a2 Can Replace Oct4 in the Reprogramming of Murine Somatic Cells to Pluripotent Cells
The Nuclear Receptor Nr5a2 Can Replace Oct4 in the Reprogramming of Murine Somatic Cells to Pluripotent Cells
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DOI：
10.1016/j.stem.2009.12.009
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发表时间：
2010-02-05
期刊：
影响因子：
23.9
通讯作者：
Ng, Huck-Hui
中科院分区：
文献类型：
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作者：
Heng, Jian-Chien Dominic;Feng, Bo;Ng, Huck-Hui
通过引入Oct4、Sox2、Klf4和c-Myc，体细胞可以重编程为诱导多能干细胞（iPSG）。在这四种因子中，Oct4在诱导多能性中是关键的，因为没有转录因子可以取代Oct4，而Sox2、Klf4和c-Myc可以被其他因子取代。在这里，我们发现孤儿核受体Nr5a2（也称为Lrh-1）可以在从小鼠体细胞衍生iPSCs中取代Oct4，并且它还可以提高重编程效率。具有增强的转录活性的Nr5a2的类小泛素化突变体可以进一步增加重编程效率。全基因组定位分析显示，Nr5a2与Sox2和Klf4共享许多共同的基因靶点，这表明转录因子三重奏协同工作以介导重编程。我们还表明，Nr5a2的工作部分通过激活Nanog。总之，我们表明，不相关的转录因子可以取代Oct4和揭示外源Oct4免费重编程代码。
Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSGs) with the introduction of Oct4, Sox2, Klf4, and c-Myc. Among these four factors, Oct4 is critical in inducing pluripotency because no transcription factor can substitute for Oct4, whereas Sox2, Klf4, and c-Myc can be replaced by other factors. Here we show that the orphan nuclear receptor Nr5a2 (also known as Lrh-1) can replace Oct4 in the derivation of iPSCs from mouse somatic cells, and it can also enhance reprogramming efficiency. Sumoylation mutants of Nr5a2 with enhanced transcriptional activity can further increase reprogramming efficiency. Genome-wide location analysis reveals that Nr5a2 shares many common gene targets with Sox2 and Klf4, which suggests that the transcription factor trio works in concert to mediate reprogramming. We also show that Nr5a2 works in part through activating Nanog. Together, we show that unrelated transcription factors can replace Oct4 and uncovers an exogenous Oct4-free reprogramming code.