Nature2014-06-19 1:24 PM

能忍受噪音的人工生物回路 Rapid and tunable post-translational coupling of genetic circuits

论文摘要 
 
合成生物学中一个主要挑战是,在一个吵杂的、高度互联的细胞环境中将各单一调控模块集成到更大回路中。Jeff Hasty及同事试图通过调用一个主体—细胞蛋白降解系统来同步基因回路的办法解决这一问题,获得的延迟时间比基于转录的耦合所实现的延迟时间短得多。然后,他们应用这一“转录后”工程方案来同步细胞时钟,使细菌群落能够在“频率多分复用”中对独立的环境提示进行回应。

Abstract 

One promise of synthetic biology is the creation of genetic circuitry that enables the execution of logical programming in living cells. Such ‘wet programming’ is positioned to transform a wide and diverse swathe of biotechnology ranging from therapeutics and diagnostics to water treatment strategies. Although progress in the development of a library of genetic modules continues apace, a major challenge for their integration into larger circuits is the generation of sufficiently fast and precise communication between modules. An attractive approach is to integrate engineered circuits with host processes that facilitate robust cellular signalling. In this context, recent studies have demonstrated that bacterial protein degradation can trigger a precise response to stress by overloading a limited supply of intracellular proteases. Here we use protease competition to engineer rapid and tunable coupling of genetic circuits across multiple spatial and temporal scales. We characterize coupling delay times that are more than an order of magnitude faster than standard transcription-factor-based coupling methods (less than 1 min compared with ~20–40 min) and demonstrate tunability through manipulation of the linker between the protein and its degradation tag. We use this mechanism as a platform to couple genetic clocks at the intracellular and colony level, then synchronize the multi-colony dynamics to reduce variability in both clocks. We show how the coupled clock network can be used to encode independent environmental inputs into a single time series output, thus enabling frequency multiplexing (information transmitted on a common channel by distinct frequencies) in a genetic circuit context. Our results establish a general framework for the rapid and tunable coupling of genetic circuits through the use of native ‘queueing’ processes such as competitive protein degradation.

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