Model-guided design of ligand-regulated RNAi for programmable control of gene expression

被引：95

作者：

Beisel, Chase L. ^{[1
]}

Bayer, Travis S. ^{[2
]}

Hoff, Kevin G. ^{[1
]}

Smolke, Christina D. ^{[1
]}

机构：

[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA

[2] CALTECH, Div Biol, Pasadena, CA 91125 USA

来源：

MOLECULAR SYSTEMS BIOLOGY | 2008年 / 4卷 / 1期

基金：

美国国家卫生研究院;

关键词：

aptamer; mathematical modelling; RNA; shRNA; synthetic biology;

D O I：

10.1038/msb.2008.62

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

Progress in constructing biological networks will rely on the development of more advanced components that can be predictably modified to yield optimal system performance. We have engineered an RNA-based platform, which we call an shRNA switch, that provides for integrated ligand control of RNA interference (RNAi) by modular coupling of an aptamer, competing strand, and small hairpin (sh) RNA stem into a single component that links ligand concentration and target gene expression levels. A combined experimental and mathematical modelling approach identified multiple tuning strategies and moves towards a predictable framework for the forward design of shRNA switches. The utility of our platform is highlighted by the demonstration of fine-tuning, multi-input control, and model-guided design of shRNA switches with an optimized dynamic range. Thus, shRNA switches can serve as an advanced component for the construction of complex biological systems and offer a controlled means of activating RNAi in disease therapeutics.

引用

页数：14

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