Ye Haifeng, Xie Mingqi, Xue Shuai, Charpin-El Hamri Ghislaine, Yin Jianli, Zulewski Henryk, Fussenegger Martin
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, 200241 Shanghai, China.
Nat Biomed Eng. 2017 Jan;1(1):0005. doi: 10.1038/s41551-016-0005. Epub 2016 Dec 19.
By using tools from synthetic biology, sophisticated genetic devices can be assembled to reprogram mammalian cell activities. Here, we demonstrate that a self-adjusting synthetic gene circuit can be designed to sense and reverse the insulin-resistance syndrome in different mouse models. By functionally rewiring the mitogen-activated protein kinase (MAPK) signalling pathway to produce MAPK-mediated activation of the hybrid transcription factor TetR-ELK1, we assembled a synthetic insulin-sensitive transcription-control device that self-sufficiently distinguished between physiological and increased blood insulin levels and correspondingly fine-tuned the reversible expression of therapeutic transgenes from synthetic TetR-ELK1-specific promoters. In acute experimental hyperinsulinemia, the synthetic insulin-sensing designer circuit reversed the insulin-resistance syndrome by coordinating expression of the insulin-sensitizing compound adiponectin. Engineering synthetic gene circuits to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide opportunities for future gene- and cell-based treatments of multifactorial metabolic disorders.
通过使用合成生物学工具，可以组装复杂的遗传装置来重新编程哺乳动物细胞的活动。在此，我们证明可以设计一种自我调节的合成基因回路，以感知并逆转不同小鼠模型中的胰岛素抵抗综合征。通过对丝裂原活化蛋白激酶（MAPK）信号通路进行功能重布线，以产生MAPK介导的杂交转录因子TetR-ELK1的激活，我们组装了一种合成胰岛素敏感转录控制装置，该装置能够自主区分生理和升高的血液胰岛素水平，并相应地微调来自合成TetR-ELK1特异性启动子的治疗性转基因的可逆表达。在急性实验性高胰岛素血症中，合成胰岛素感应设计回路通过协调胰岛素增敏化合物脂联素的表达逆转了胰岛素抵抗综合征。设计合成基因回路以感知病理标志物并协调治疗性转基因的表达，可能为未来基于基因和细胞的多因素代谢紊乱治疗提供机会。
