可重用可组合的转录逻辑门设计
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摘要
目前复杂的合成基因网络的研究面临的一个困难是缺乏诸如可以处理组合信号的转录逻辑门这样的基本组件。本文中我们提出一种可重复使用的转录逻辑门设计策略：对已深入研究的自然转录系统进行迭代重设计,重构其型号识别特异性,并基于启动子区域的顺式相互作用构建可以处理组合信号的转录逻辑门。我们利用从特异性相互作用对中挑选出的转录因子LacI及其操纵基因Olac的变体,演示如何在数学模型的辅助下,从已有的定量知识中,理性设计和实现转录的NAND, NOR和NOR门。其中NAND门利用蛋白间相互作用实现DNA成环效应。我们演示了这种设计是可重复使用的：同一设计可以产生多种相似的逻辑组件,仅仅替换其中的操纵基因的组合就可以改变上游的组合信号。我们可以将这些逻辑门组合起来以产生复杂的基因网络：我们演示和一个包含所有三种设计的逻辑门的现实逻辑网络的合成和测试,它能重现设定的输入-输出逻辑规则。
One limit on developing complex synthetic gene circuits is the lack of basic components such as transcriptional logic gates that can process combinatorial in-puts. Here we propose a strategy to construct such components based on reusable designs and convergent reengineering of well-studied natural systems. We demon-strated the strategy using variants of the transcription factor LacI and operator Olac that form specifically interacting pairs. Guided by a mathematical model derived from existing quantitative knowledge, rational designs of transcriptional NAND, NOR and NOT gates have been realized. The NAND gates have been de-signed based on direct protein-protein interactions in coupling with DNA looping. We demonstrated that the designs are reusable:a multiplex of logic devices can be readily created using the same designs but different combinations of sequence variants. The designed logic gates are combinable to form compound circuits:a demonstration logic circuit containing all three types of designed logic gates has been synthesized, and the circuit truthfully reproduces the pre-designed input-output logic relations.
One limit on developing complex synthetic gene circuits is the lack of basic components such as transcriptional logic gates that can process combinatorial in-puts. Here we propose a strategy to construct such components based on reusable designs and convergent reengineering of well-studied natural systems. We demon-strated the strategy using variants of the transcription factor LacI and operator Olac that form specifically interacting pairs. Guided by a mathematical model derived from existing quantitative knowledge, rational designs of transcriptional NAND, NOR and NOT gates have been realized. The NAND gates have been de-signed based on direct protein-protein interactions in coupling with DNA looping. We demonstrated that the designs are reusable:a multiplex of logic devices can be readily created using the same designs but different combinations of sequence variants. The designed logic gates are combinable to form compound circuits:a demonstration logic circuit containing all three types of designed logic gates has been synthesized, and the circuit truthfully reproduces the pre-designed input-output logic relations.
引文
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