Effects of the spatial distribution of resources on the performance of genetic circuits

转录和翻译资源的可用性在基因表达中起着重要作用，是影响合成遗传回路和代谢途径性能的关键因素。虽然对生长、细胞基因表达能力和细胞资源分配之间的权衡进行了广泛的研究，但对这些资源的空间分布如何影响基因表达知之甚少。与通常的假设相反，即使是像细菌这样缺乏细胞器的简单细胞也是异质的，远离发生生化反应的混合良好的血管。特别是，已经证明，具有良好特征的微生物，如大肠杆菌，具有转录和翻译机制的非均匀分布。在这个项目中，我们将研究基因的细胞质位置和表达所需的资源如何影响遗传回路的性能。一些开创性的研究表明，考虑到转录调节因子等分子需要扩散到细胞的不同区域，构成同一回路的基因之间的距离会影响它们的动态行为。同样，非均匀分布的核糖体和RNA聚合酶需要扩散到产生相关mrna和蛋白质的细胞位置。我们假设对资源的“本地”需求在决定感兴趣基因的最终表达水平方面起着作用。因此，考虑空间作为设计变量是合成生物学的一个新方面，我们将在这个项目中进行评估。

The availability of transcriptional and translational resources plays an important role in gene expression and is a key factor affecting the performance of synthetic genetic circuits and metabolic pathways. While there are extensive investigations of trade-offs between growth, cellular capacity for gene expression and allocation of cellular resources, little is known about how the spatial distribution of these resources impacts gene expression. Contrary to common assumptions, even simple cells lacking organelles like bacteria are heterogenous and far from well-mixed vessels where biochemical reactions take place. In particular, it has been demonstrated that well-characterised microorganisms such as Escherichia coli have a non-homogenous distribution of the transcriptional and translational machinery.In this project we will investigate how the cytoplasmic location of the genes and the resources required for expression affect the performance of genetic circuits. Some pioneering works show that the distance between genes composing the same circuit influences their dynamic behaviour given that molecules such as transcriptional regulators need to diffuse to different regions of the cell2. Likewise, non-homogeneously distributed ribosomes and RNA polymerases need to diffuse to the locations of the cell at which the relevant mRNAs and proteins are produced. We hypothesise that the 'local' demand for resources plays a role in determining the final expression levels of genes of interest. Considering space as a design variable is, therefore, a novel aspect of synthetic biology that we will assess in this project.