Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch
Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch
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DOI：
10.1016/j.bpj.2017.12.010
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发表时间：
2018-02-06
影响因子：
3.4
通讯作者：
Lu, Ting
中科院分区：
文献类型：
--
作者：
Blanchard, Andrew E.;Liao, Chen;Lu, Ting
基因电路的定量建模对合成生物学至关重要，因为它提供了将电路工程从试错构建转变为理性设计的潜力，因此促进了该领域的发展。目前，典型的模型将基因电路视为孤立的实体，只关注电路内的生化过程。然而，越来越多的实验证据表明，电路和它们的宿主是紧密相连的，它们的相互作用可能会影响电路的行为，这对这种标准范式提出了挑战。本文以自激活基因开关为模型电路，系统地研究了电路-宿主耦合在形成电路动力学中的作用。通过结合确定性建模，随机模拟，和福克-普朗克方程形式主义，我们发现，电路主机耦合改变开关行为在多个尺度。在单细胞水平上，它减缓了高蛋白质生产机制中的转换动力学，并扩大了稳定稳态值之间的差异。在群体水平上，它通过差异生长扩增有利于蛋白质产量低的细胞。总之，两级耦合效应引起开关的定量和定性调制，其中效应的主要分量由电路的结构参数确定。这项研究说明了电路-宿主耦合在调制电路行为中的复杂性和重要性，表明需要一个新的范式-电路-宿主系统的集成建模-用于定量理解工程基因网络。
Quantitative modeling of gene circuits is fundamentally important to synthetic biology, as it offers the potential to transform circuit engineering from trial-and-error construction to rational design and, hence, facilitates the advance of the field. Currently, typical models regard gene circuits as isolated entities and focus only on the biochemical processes within the circuits. However, such a standard paradigm is getting challenged by increasing experimental evidence suggesting that circuits and their host are intimately connected, and their interactions can potentially impact circuit behaviors. Here we systematically examined the roles of circuit-host coupling in shaping circuit dynamics by using a self-activating gene switch as a model circuit. Through a combination of deterministic modeling, stochastic simulation, and Fokker-Planck equation formalism, we found that circuit-host coupling alters switch behaviors across multiple scales. At the single-cell level, it slows the switch dynamics in the high protein production regime and enlarges the difference between stable steady-state values. At the population level, it favors cells with low protein production through differential growth amplification. Together, the two-level coupling effects induce both quantitative and qualitative modulations of the switch, with the primary component of the effects determined by the circuit's architectural parameters. This study illustrates the complexity and importance of circuit-host coupling in modulating circuit behaviors, demonstrating the need for a new paradigm-integrated modeling of the circuit-host system-for quantitative understanding of engineered gene networks.