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Generating effective models and parameters for RNA genetic circuits

Chelsea Y. Hu, Jeffrey D. Varner, Julius B. Lucks
doi: https://doi.org/10.1101/018358
Chelsea Y. Hu
1School of Chemical and Biomolecular Engineering, Cornell University, Ithaca NY 14850
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Jeffrey D. Varner
1School of Chemical and Biomolecular Engineering, Cornell University, Ithaca NY 14850
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Julius B. Lucks
1School of Chemical and Biomolecular Engineering, Cornell University, Ithaca NY 14850
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Abstract

RNA genetic circuitry is emerging as a powerful tool to control gene expression. However, little work has been done to create a theoretical foundation for RNA circuit design. A prerequisite to this is a quantitative modeling framework that accurately describes the dynamics of RNA circuits. In this work, we develop an ordinary differential equation model of transcriptional RNA genetic circuitry, using an RNA cascade as a test case. We show that parameter sensitivity analysis can be used to design a set of four simple experiments that can be performed in parallel using rapid cell-free transcription-translation (TX-TL) reactions to determine the thirteen parameters of the model. The resulting model accurately recapitulates the dynamic behavior of the cascade, and can be easily extended to predict the function of new cascade variants that utilize new elements with limited additional characterization experiments. Interestingly, we show that inconsistencies between model predictions and experiments led to the model-guided discovery of a previously unknown maturation step required for RNA regulator function. We also determine circuit parameters in two different batches of TX-TL, and show that batch-to-batch variation can be attributed to differences in parameters that are directly related to the concentrations of core gene expression machinery. We anticipate the RNA circuit models developed here will inform the creation of computer aided genetic circuit design tools that can incorporate the growing number of RNA regulators, and that the parameterization method will find use in determining functional parameters of a broad array of natural and synthetic regulatory systems.

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Posted April 21, 2015.
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Generating effective models and parameters for RNA genetic circuits
Chelsea Y. Hu, Jeffrey D. Varner, Julius B. Lucks
bioRxiv 018358; doi: https://doi.org/10.1101/018358
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Generating effective models and parameters for RNA genetic circuits
Chelsea Y. Hu, Jeffrey D. Varner, Julius B. Lucks
bioRxiv 018358; doi: https://doi.org/10.1101/018358

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