Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Nat Microbiol. 2024 Aug;9(8):2173-2184. doi: 10.1038/s41564-024-01706-w. Epub 2024 Jun 18.
Natural microbial populations exploit phenotypic heterogeneity for survival and adaptation. However, in engineering biology, limiting the sources of variability is a major focus. Here we show that intentionally coupling distinct plasmids via shared replication mechanisms enables bacterial populations to adapt to their environment. We demonstrate that plasmid coupling of carbon-metabolizing operons facilitates copy number tuning of an essential but burdensome construct through the action of a stably maintained, non-essential plasmid. For specific cost-benefit situations, incompatible two-plasmid systems can stably persist longer than compatible ones. We also show using microfluidics that plasmid coupling of synthetic constructs generates population-state memory of previous environmental adaptation without additional regulatory control. This work should help to improve the design of synthetic populations by enabling adaptive engineered strains to function under changing growth conditions without strict fine-tuning of the genetic circuitry.
自然微生物种群利用表型异质性来生存和适应。然而，在工程生物学中，限制变异性的来源是一个主要关注点。在这里，我们表明，通过共享复制机制有意地将不同的质粒连接起来，可以使细菌种群适应其环境。我们证明，通过稳定维持的非必需质粒的作用，碳代谢操纵子的质粒偶联促进了必需但负担重的构建体的拷贝数调谐。对于特定的成本效益情况，不兼容的双质粒系统比兼容的系统更稳定地持续存在。我们还使用微流控技术表明，合成构建体的质粒偶联在没有额外调控控制的情况下，会产生对先前环境适应的种群状态记忆。这项工作应该有助于通过使适应性工程菌株在不断变化的生长条件下发挥作用，而无需对遗传电路进行严格的微调，从而改进合成种群的设计。
