期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8148-8153
DOI：10.1073/pnas.1423947112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSystem identification addresses the problem of identifying unknown model parameters from measured data of a real system. In the case of biochemical reaction networks, the available measurements are typically sparse because of technical and/or economic reasons. Therefore, it is of paramount importance to maximize the information that can be gained by each experiment. Here, we apply a systematic design scheme for single-cell experiments based on information theoretic criteria. For the considered light-inducible gene expression circuit, we show that this scheme allows one to precisely identify model parameters that were practically unidentifiable from data measured in random experiments. This result provides evidence that optimal experiment design is a key requirement for the successful identification of biochemical reaction networks. Systems biology rests on the idea that biological complexity can be better unraveled through the interplay of modeling and experimentation. However, the success of this approach depends critically on the informativeness of the chosen experiments, which is usually unknown a priori. Here, we propose a systematic scheme based on iterations of optimal experiment design, flow cytometry experiments, and Bayesian parameter inference to guide the discovery process in the case of stochastic biochemical reaction networks. To illustrate the benefit of our methodology, we apply it to the characterization of an engineered light-inducible gene expression circuit in yeast and compare the performance of the resulting model with models identified from nonoptimal experiments. In particular, we compare the parameter posterior distributions and the precision to which the outcome of future experiments can be predicted. Moreover, we illustrate how the identified stochastic model can be used to determine light induction patterns that make either the average amount of protein or the variability in a population of cells follow a desired profile. Our results show that optimal experiment design allows one to derive models that are accurate enough to precisely predict and regulate the protein expression in heterogeneous cell populations over extended periods of time.
关键词：stochastic kinetic models ; optimal experiment design ; in vivo control ; parameter inference ; light-induced gene expression
