Using a quantitative blueprint to reprogram the dynamics of the flagella gene network
Using a quantitative blueprint to reprogram the dynamics of the flagella gene network
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DOI：
10.1016/j.cell.2004.05.010
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发表时间：
2004-06-11
期刊：
影响因子：
64.5
通讯作者：
Alon, U
中科院分区：
文献类型：
--
作者：
Kalir, S;Alon, U
对生物网络的详细理解和控制将需要类似于电子工程蓝图的描述水平。然而，目前，即使是研究得最好的系统也通常使用定性箭头图来描述。定量蓝图需要体内测量（1）相互作用的相对强度（箭头上的数字）和（2）整合多个输入的函数。在这里，我们使用一个经过充分研究的系统来解决这个问题，即大肠杆菌中的鞭毛生物合成转录网络。我们利用理论和高分辨率实验获得了定量蓝图（1）箭头上的数字，找到了两种调节器 FlhDC 和 FliA 的不同激活系数层次； (2) 顺式调节输入函数，将两个调节器（SUM 门）的输入相加。然后，我们通过实验证明了如何使用该蓝图来重新编程该系统中的时间表达模式，使用调节因子的受控表达或其结合位点的点突变。本方法可用于定义其他基因网络的蓝图并定量地重新编程其动态。
Detailed understanding and control of biological networks will require a level of description similar to that of electronic engineering blueprints. Currently, however, even the best-studied systems are usually described using qualitative arrow diagrams. A quantitative blueprint requires in vivo measurements of (1) the relative strength of the interactions (numbers on the arrows) and (2) the functions that integrate multiple inputs. Here, we address this using a well-studied system, the flagella biosynthesis transcription network in Escherichia coli. We use theory and high-resolution experiments to obtain a quantitative blueprint with (1) numbers on the arrows, finding different hierarchies of activation coefficients for the two regulators, FlhDC and FliA; and (2) cis-regulatory input functions, which summate the input from the two regulators (SUM gates). We then demonstrate experimentally how this blueprint can be used to reprogram temporal expression patterns in this system, using controlled expression of the regulators or point mutations in their binding sites. The present approach can be used to define blueprints of other gene networks and to quantitatively reprogram their dynamics.