Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks
Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks
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DOI：
10.1038/ncb1775
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发表时间：
2008-10-01
影响因子：
21.3
通讯作者：
Ueda, Hiroki R.
中科院分区：
文献类型：
--
作者：
Ukai-Tadenuma, Maki;Kasukawa, Takeya;Ueda, Hiroki R.
哺乳动物的生物钟由复杂的调节回路组成，至少通过早晨、白天和夜晚的DNA元素进行调节。为了证明哺乳动物时钟的转录逻辑，我们开发了一个细胞内哺乳动物细胞培养系统，使我们能够设计和实现人工转录电路。在这里，我们发现早晨激活和夜间抑制可以在白天产生转录输出，同样，白天激活和早晨抑制可以在夜间产生转录输出。我们还观察到，通过转录激活因子和转录抑制因子的简单组合表达，可以产生其他阶段的多种转录输出。这些结果揭示了设计原则，不仅可以理解在体内观察到的连续转录输出，还可以用于在新阶段工作的人工启动子的逻辑构建。人工电路的逻辑合成，具有确定的结构和观察到的动力学，提供了一种适用于复杂生物系统研究的替代策略。
Mammalian circadian clocks consist of complex regulatory loops mediated through-at least-morning, daytime and night-time DNA elements. To prove the transcriptional logic of mammalian clocks, we developed an in cellulo mammalian cell-culture system that allowed us to design and implement artificial transcriptional circuits. Here we show that morning activation and night-time repression can yield the transcriptional output during the daytime, and similarly that daytime activation and morning repression can yield night-time transcriptional output. We also observed that the diverse transcriptional outputs of other phases can be generated through the expression of simple combinations of transcriptional activators and repressors. These results reveal design principles not only for understanding the continuous transcriptional outputs observed in vivo but also for the logical construction of artificial promoters working at novel phases. Logical synthesis of artificial circuits, with an identified structure and observed dynamics, provides an alternative strategy applicable to the investigation of complex biological systems.