Circuit-level input integration in bacterial gene regulation
Circuit-level input integration in bacterial gene regulation
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DOI：
10.1073/pnas.1216091110
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发表时间：
2013-04-23
影响因子：
11.1
通讯作者：
Garcia-Ojalvo, Jordi
中科院分区：
文献类型：
--
作者：
Espinar, Lorena;Dies, Marta;Garcia-Ojalvo, Jordi
基因调控电路可以同时接收多个输入，这些输入可以通过不同的位置进入系统。因此，有必要确定这些遗传电路如何将多个输入作为其相对入口点的函数进行整合。在这里，我们使用枯草芽孢杆菌 DNA 摄取的动态回路调节能力作为模型系统来研究这个问题。具体来说，我们将体内单细胞的反应映射到以下组合：（i）控制关键能力基因组成型表达的化学信号，以及（ii）这些基因之一的拷贝数变异形式的遗传扰动，模拟细菌感知的应激信号水平。定量延时荧光显微镜表明，两种输入的组合可以实现多种动力学行为。此外，积分很大程度上取决于两个扰动进入电路的相对位置。具体来说，当两个输入作用于不同的电路元件时，它们的集成会产生新颖的动态行为，而影响同一元件的输入则不会。电路数学模型的计算机二维分岔分析提供了与实验观察良好的定量一致性，并揭示了导致基因调控电路表现出不同综合反应的动力学机制。
Gene regulatory circuits can receive multiple simultaneous inputs, which can enter the system through different locations. It is thus necessary to establish how these genetic circuits integrate multiple inputs as a function of their relative entry points. Here, we use the dynamic circuit regulating competence for DNA uptake in Bacillus subtilis as a model system to investigate this issue. Specifically, we map the response of single cells in vivo to a combination of (i) a chemical signal controlling the constitutive expression of key competence genes, and (ii) a genetic perturbation in the form of copy number variation of one of these genes, which mimics the level of stress signals sensed by the bacteria. Quantitative time-lapse fluorescence microscopy shows that a variety of dynamical behaviors can be reached by the combination of the two inputs. Additionally, the integration depends strongly on the relative locations where the two perturbations enter the circuit. Specifically, when the two inputs act upon different circuit elements, their integration generates novel dynamical behavior, whereas inputs affecting the same element do not. An in silico bidimensional bifurcation analysis of a mathematical model of the circuit offers good quantitative agreement with the experimental observations, and sheds light on the dynamical mechanisms leading to the different integrated responses exhibited by the gene regulatory circuit.