Resource Competition Shapes the Response of Genetic Circuits
Resource Competition Shapes the Response of Genetic Circuits
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DOI：
10.1021/acssynbio.6b00361
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发表时间：
2017-07-01
影响因子：
4.7
通讯作者：
Del Vecchio, Domitilla
中科院分区：
文献类型：
--
作者：
Qian, Yili;Huang, Hsin-Ho;Del Vecchio, Domitilla
设计基因电路的一种常见方法是将基因表达盒组合在一起。虽然有吸引力，这种模块化的方法是挑战的事实，即每个基因的表达取决于转录/翻译资源的可用性，这反过来又决定了电路中的其他基因的存在。这就提出了一个问题，即不同基因对资源的竞争如何影响电路的行为。在这里，我们创建了一个库的基因激活级联在E。大肠杆菌中，我们明确调整每个基因的资源需求。我们开发了一个通用的希尔函数为基础的模型，通过资源需求系数，将资源竞争的影响。这些系数导致基因之间的非调节性相互作用，重塑电路行为。对于激活级联，这种相互作用导致令人惊讶的双相或单调递减的反应。最后，我们使用资源需求系数来指导核糖体结合位点和DNA拷贝数的选择，以恢复预期的单调递增响应级联。我们的研究结果表明，意外的电路行为是如何产生的资源竞争，并提供了一个模型指导的方法，以尽量减少由此产生的影响。
A common approach to design genetic circuits is to compose gene expression cassettes together. While appealing, this modular approach is challenged by the fact that expression of each gene depends on the availability of transcriptional/translational resources, which is in turn determined by the presence of other genes in the circuit. This raises the question of how competition for resources by different genes affects a circuits behavior. Here, we create a library of genetic activation cascades in E. coli bacteria, where we explicitly tune the resource demand by each gene. We develop a general Hill-function-based model that incorporates resource competition effects through resource demand coefficients. These coefficients lead to nonregulatory interactions among genes that reshape the circuits behavior. For the activation cascade, such interactions result in surprising biphasic or monotonically decreasing responses. Finally, we use resource demand coefficients to guide the choice of ribosome binding site and DNA copy number to restore the cascades intended monotonically increasing response. Our results demonstrate how unintended circuits behavior arises from resource competition and provide a model-guided methodology to minimize the resulting effects.