Multistability in the lactose utilization network of Escherichia coli
Multistability in the lactose utilization network of Escherichia coli
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DOI：
10.1038/nature02298
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发表时间：
2004-02-19
期刊：
影响因子：
64.8
通讯作者：
van Oudenaarden, A
中科院分区：
文献类型：
--
作者：
Ozbudak, EM;Thattai, M;van Oudenaarden, A
多稳定性，即在响应单一外部输入时实现多种内部状态的能力，是开关的定义特性。在多细胞生物中，生物开关对于决定细胞命运至关重要(1)，在有丝分裂过程中调节细胞周期振荡（2,3），以及维持微生物的表观遗传性状(4)。几种自然（1-6）和合成（7-9）系统的多稳定性归因于其调节网络中的正反馈回路（10）。然而，单靠反馈并不能保证多稳定性。多稳定系统的相图是对内部状态作为关键参数变化的简明描述，揭示了产生功能开关所需的条件（11,12）。在这里，我们给出了大肠杆菌双稳态乳糖利用网络的相图（13）。我们使用这个相图，结合网络的数学模型，定量研究体内糖摄取和转录调节等过程。然后，我们展示了如何将野生型系统的滞后响应转换为超灵敏的分级响应（14,15）。因此，相图作为分子相互作用的敏感探针和合理网络设计的有力工具。
Multistability, the capacity to achieve multiple internal states in response to a single set of external inputs, is the defining characteristic of a switch. Biological switches are essential for the determination of cell fate in multicellular organisms(1), the regulation of cell-cycle oscillations during mitosis(2,3) and the maintenance of epigenetic traits in microbes(4). The multistability of several natural(1-6) and synthetic(7-9) systems has been attributed to positive feedback loops in their regulatory networks(10). However, feedback alone does not guarantee multistability. The phase diagram of a multistable system, a concise description of internal states as key parameters are varied, reveals the conditions required to produce a functional switch(11,12). Here we present the phase diagram of the bistable lactose utilization network of Escherichia coli(13). We use this phase diagram, coupled with a mathematical model of the network, to quantitatively investigate processes such as sugar uptake and transcriptional regulation in vivo. We then show how the hysteretic response of the wildtype system can be converted to an ultrasensitive graded response(14,15). The phase diagram thus serves as a sensitive probe of molecular interactions and as a powerful tool for rational network design.