Feng Bo, Jiang Jianming, Kraus Petra, Ng Jia-Hui, Heng Jian-Chien Dominic, Chan Yun-Shen, Yaw Lai-Ping, Zhang Weiwei, Loh Yuin-Han, Han Jianyong, Vega Vinsensius B, Cacheux-Rataboul Valere, Lim Bing, Lufkin Thomas, Ng Huck-Hui
Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672.
Nat Cell Biol. 2009 Feb;11(2):197-203. doi: 10.1038/ncb1827. Epub 2009 Jan 11.
The dominant effect of transcription factors in imparting expanded potency is best exemplified by the reprogramming of fibroblasts to pluripotent cells using retrovirus-mediated transduction of defined transcription factors. In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that have many characteristics of embryonic stem (ES) cells. Here we show that the orphan nuclear receptor Esrrb functions in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb-reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimaeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in self-renewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the upregulation of ES-cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming.
转录因子在赋予细胞扩展潜能方面的主导作用，最典型的例子是利用逆转录病毒介导特定转录因子的转导，将成纤维细胞重编程为多能细胞。在小鼠系统中，Oct4、Sox2、c-Myc和Klf4足以将成纤维细胞转化为具有许多胚胎干细胞（ES细胞）特征的诱导多能干细胞（iPS细胞）。在此我们表明，孤儿核受体Esrrb与Oct4和Sox2协同作用，介导小鼠胚胎成纤维细胞（MEF）重编程为iPS细胞。Esrrb重编程的细胞与ES细胞具有相似的表达和表观遗传特征。这些细胞也是多能的，能够在体外和体内分化为三个主要的胚胎细胞谱系。此外，这些细胞可形成小鼠嵌合体并可进行种系传递。在ES细胞中，Esrrb靶向许多参与自我更新和多能性的基因。这表明Esrrb可能通过上调ES细胞特异性基因来介导重编程。我们的研究结果还表明，无需外源性Klf转录因子即可对MEF进行重编程，并将一种核受体与体细胞重编程联系起来。
