Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Science. 2013 Sep 20;341(6152):1235005. doi: 10.1126/science.1235005. Epub 2013 Aug 15.
Engineering of cell fate through synthetic gene circuits requires methods to precisely implement control around native decision-making pathways and offers the potential to direct cell processes. We demonstrate a class of genetic control systems, molecular network diverters, that interface with a native signaling pathway to route cells to divergent fates in response to environmental signals without modification of native genetic material. A method for identifying control points within natural networks is described that enables the construction of synthetic control systems that activate or attenuate native pathways to direct cell fate. We integrate opposing genetic programs by developing network architectures for reduced antagonism and demonstrate rational tuning of performance. Extension of these control strategies to mammalian systems should facilitate the engineering of complex cellular signaling systems.
通过合成基因回路来设计细胞命运需要精确控制天然决策途径的方法，这为指导细胞过程提供了可能。我们展示了一类遗传控制系统，即分子网络分流器，它与天然信号通路接口，能够根据环境信号将细胞引导至不同的命运，而无需对天然遗传物质进行修饰。本文描述了一种在天然网络中识别控制点的方法，该方法能够构建激活或衰减天然途径以指导细胞命运的合成控制系统。我们通过开发减少拮抗作用的网络架构来整合相反的遗传程序，并展示了性能的合理调整。将这些控制策略扩展到哺乳动物系统中，应该有助于设计复杂的细胞信号系统。
