MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland.
EMBO J. 2012 Dec 12;31(24):4547-62. doi: 10.1038/emboj.2012.321. Epub 2012 Nov 23.
NANOG, OCT4 and SOX2 form the core network of transcription factors supporting embryonic stem (ES) cell self-renewal. While OCT4 and SOX2 expression is relatively uniform, ES cells fluctuate between states of high NANOG expression possessing high self-renewal efficiency, and low NANOG expression exhibiting increased differentiation propensity. NANOG, OCT4 and SOX2 are currently considered to activate transcription of each of the three genes, an architecture that cannot readily account for NANOG heterogeneity. Here, we examine the architecture of the Nanog-centred network using inducible NANOG gain- and loss-of-function approaches. Rather than activating itself, Nanog activity is autorepressive and OCT4/SOX2-independent. Moreover, the influence of Nanog on Oct4 and Sox2 expression is minimal. Using Nanog:GFP reporters, we show that Nanog autorepression is a major regulator of Nanog transcription switching. We conclude that the architecture of the pluripotency gene regulatory network encodes the capacity to generate reversible states of Nanog transcription via a Nanog-centred autorepressive loop. Therefore, cellular variability in self-renewal efficiency is an emergent property of the pluripotency gene regulatory network.
NANOG、OCT4 和 SOX2 形成了支持胚胎干细胞（ES 细胞）自我更新的转录因子核心网络。虽然 OCT4 和 SOX2 的表达相对均匀，但 ES 细胞在高 NANOG 表达状态（具有高自我更新效率）和低 NANOG 表达状态（表现出增加的分化倾向）之间波动。NANOG、OCT4 和 SOX2 目前被认为激活了这三个基因的转录，这种结构不能很好地解释 NANOG 的异质性。在这里，我们使用诱导型 NANOG 增益和缺失功能方法来研究以 NANOG 为中心的网络的结构。NANOG 活性不是自我激活的，而是自我抑制的，且不依赖于 OCT4/SOX2。此外，Nanog 对 Oct4 和 Sox2 表达的影响很小。通过 Nanog:GFP 报告基因，我们表明 Nanog 自我抑制是 Nanog 转录开关的主要调节因子。我们得出结论，多能性基因调控网络的结构通过以 Nanog 为中心的自我抑制环赋予了生成 Nanog 转录可逆状态的能力。因此，自我更新效率的细胞变异性是多能性基因调控网络的一个突现属性。
