Multi-variable control to mitigate loads in CRISPRa networks

Krishna Manoj, Theodore W. Grunberg, Domitilla Del Vecchio
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Abstract

The discovery of CRISPR-mediated gene activation (CRISPRa) has transformed the way in which we perform genetic screening, bioproduction and therapeutics through its ability to scale and multiplex. However, the emergence of loads on the key molecular resources constituting CRISPRa by the orthogonal short RNA that guide such resources to gene targets, couple theoretically independent CRISPRa modules. This coupling negates the ability of CRISPRa systems to concurrently regulate multiple genes independent of one another. In this paper, we propose to reduce this coupling by mitigating the loads on the molecular resources that constitute CRISPRa. In particular, we design a multi-variable controller that makes the concentration of these molecular resources robust to variations in the level of the short RNA loads. This work serves as a foundation to design and implement CRISPRa controllers for practical applications.
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多变量控制减轻 CRISPRa 网络的负载
CRISPR-mediated gene activation(CRISPRa)的发现改变了我们进行基因筛选、生物生产和治疗的方式,因为它具有规模化和多重化的能力。然而,由于正交短 RNA 引导 CRISPRa 的关键分子资源到达基因靶点,使理论上独立的 CRISPRa 模块出现了负载。这种耦合否定了 CRISPRa 系统同时独立调控多个基因的能力。在本文中,我们建议通过减轻构成 CRISPRa 的分子资源的负荷来减少这种耦合。特别是,我们设计了一个多变量控制器,使这些分子资源的浓度对短 RNA 负载水平的变化具有稳健性。这项工作为设计和实现实际应用中的 CRISPRa 控制器奠定了基础。
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