Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.
Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.
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DOI：
10.1371/journal.pone.0150715
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ema M
中科院分区：
文献类型：
--
作者：
Jeon H;Waku T;Azami T;Khoa le TP;Yanagisawa J;Takahashi S;Ema M
在小鼠胚胎干细胞中维持多能性，并通过激活适当的转录调控网络从体细胞诱导。KLF2、KLF4和KLF5等KRüppel样因子家族成员在维持小鼠ES细胞的未分化状态和细胞重编程中发挥着重要作用，但目前尚不清楚其他KLf家族成员在过度表达时是否具有自我更新和重编程功能。在这项研究中，我们检测了任何具有代表性的KLF家族成员，如KLF1-KLF10的过度表达是否足以使小鼠ES细胞自我更新。我们发现只有KLF2、KLF4和KLF5产生非依赖于白血病抑制因子(LIF)的自我更新，尽管大多数KLF蛋白(如果不是全部的话)都有能力占据关键的KLF靶基因Nanog的调节区。我们还研究了KLF1-KLF10的过度表达是否足以将上皮样干细胞转化为幼稚的多能性状态，发现除了KLF2和KLF4外，KLF5还具有这种重编程能力。我们还描绘了KLF2蛋白的功能结构域，用于LIF非依赖性的自我更新和重新编程。有趣的是，我们发现N端的转录激活和C端的锌指结构域都是这种活动所必需的。综上所述，我们的综合分析为KLF家族成员在小鼠ES自我更新和细胞重编程中的贡献提供了新的见解。
Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1–Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.