A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal
A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal
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DOI：
10.1096/fj.05-5543fje
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发表时间：
2006-08-01
期刊：
影响因子：
4.8
通讯作者：
Pei, Duanqing
中科院分区：
文献类型：
--
作者：
Pan, Guangjin;Li, Jun;Pei, Duanqing
胚胎干细胞（ES细胞）具有自我更新的能力，同时保持分化为身体几乎所有细胞类型的能力。目前的证据表明，ES细胞通过表达一系列转录因子（包括Oct 4和Nanog）来维持其多能状态。然而，关于ES细胞如何维持这些多能因子在ES细胞中的表达知之甚少。在这里，我们提出的证据表明，Oct 4，Nanog和FoxD 3形成一个负反馈回路，以维持其在多能ES细胞中的表达。首先，Oct 4通过在亚稳态浓度下直接激活其启动子，但在稳态水平或高于稳态水平下抑制它来维持Nanog活性。另一方面，FoxD 3表现为Nanog的正激活剂，以对抗Oct 4的抑制作用。Oct 4的表达被FoxD 3和Nanog激活，但被Oct 4本身抑制，因此，施加重要的负反馈回路来限制其自身的活性。事实上，FoxD 3或Nanog在ES细胞中的过表达未能使Oct 4的浓度增加超过稳态浓度，而敲低FoxD 3或Nanog降低了Oct 4在ES细胞中的表达。最后，Oct 4或Nanog的过表达未能分别补偿Nanog或Oct 4的损失，这表明两者都是ES自我更新和多能性所需的。我们的研究结果表明，FoxD 3-Nanog-Oct 4环锚定了一个相互依赖的转录因子网络，调节干细胞多能性。
Embryonic stem (ES) cells possess the ability to renew themselves while maintaining the capacity to differentiate into virtually all cell types of the body. Current evidence suggests that ES cells maintain their pluripotent state by expressing a battery of transcription factors including Oct4 and Nanog. However, little is known about how ES cells maintain the expression of these pluripotent factors in ES cells. Here we present evidence that Oct4, Nanog, and FoxD3 form a negative feedback loop to maintain their expression in pluripotent ES cells. First, Oct4 maintains Nanog activity by directly activating its promoter at sub-steady-state concentration but repressing it at or above steady-state levels. On the other hand, FoxD3 behaves as a positive activator of Nanog to counter the repressive effect of Oct4. The expression of Oct4 is activated by FoxD3 and Nanog but repressed by Oct4 itself, thus, exerting an important negative feedback loop to limit its own activity. Indeed, overexpression of either FoxD3 or Nanog in ES cells failed to increase the concentration of Oct4 beyond the steady-state concentration, whereas knocking down either FoxD3 or Nanog reduces the expression of Oct4 in ES cells. Finally, overexpression of Oct4 or Nanog failed to compensate the loss of Nanog or Oct4, respectively, suggesting that both are required for ES self-renewal and pluripotency. Our results suggest the FoxD3-Nanog-Oct4 loop anchors an interdependent network of transcription factors that regulate stem cell pluripotency.