Jiang Jianming, Chan Yun-Shen, Loh Yuin-Han, Cai Jun, Tong Guo-Qing, Lim Ching-Aeng, Robson Paul, Zhong Sheng, Ng Huck-Hui
Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672.
Nat Cell Biol. 2008 Mar;10(3):353-60. doi: 10.1038/ncb1698. Epub 2008 Feb 10.
Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely and maintain pluripotency. These properties require transcription factors that specify the gene expression programme of ES cells. It has been possible to reverse the highly differentiated state of somatic cells back to a pluripotent state with a combination of four transcription factors: Klf4 is one of the reprogramming factors required, in conjunction with Oct4, Sox2 and c-Myc. Maintenance of self-renewal and pluripotency of ES cells requires Oct4, Sox2 and c-Myc, but Klf4 is dispensable. Here, we show that Krüppel-like factors are required for the self-renewal of ES cells. Simultaneous depletion of Klf2, Klf4 and Klf5 lead to ES cell differentiation. Chromatin immunoprecipitation coupled to microarray assay reveals that these Klf proteins share many common targets of Nanog, suggesting a close functional relationship between these factors. Expression analysis after triple RNA interference (RNAi) of the Klfs shows that they regulate key pluripotency genes, such as Nanog. Taken together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression that is unique to ES cells.
胚胎干细胞（ES细胞）具有无限自我更新并维持多能性的独特能力。这些特性需要特定的转录因子来确定ES细胞的基因表达程序。通过四种转录因子的组合，已能够将体细胞的高度分化状态逆转回多能状态：Klf4是所需的重编程因子之一，与Oct4、Sox2和c-Myc共同作用。ES细胞自我更新和多能性的维持需要Oct4、Sox2和c-Myc，但Klf4并非必需。在此，我们表明Krüppel样因子是ES细胞自我更新所必需的。同时缺失Klf2、Klf4和Klf5会导致ES细胞分化。染色质免疫沉淀结合微阵列分析表明，这些Klf蛋白与Nanog有许多共同靶点，提示这些因子之间存在密切的功能关系。对Klf进行三重RNA干扰（RNAi）后的表达分析表明，它们调控关键的多能性基因，如Nanog。综上所述，我们的研究为核心Klf调控途径如何整合到Nanog转录网络以确定ES细胞特有的基因表达提供了新的见解。
