Inferring dynamic gene networks under varying conditions for transcriptomic network comparison

Abstract

Elucidating the differences between cellular responses to various biological conditions or external stimuli is an important challenge in systems biology. Many approaches have been developed to reverse engineer a cellular system, called gene network, from time series microarray data in order to understand a transcriptomic response under a condition of interest. Comparative topological analysis has also been applied based on the gene networks inferred independently from each of the multiple time series datasets under varying conditions to find critical differences between these networks. However, these comparisons often lead to misleading results, because each network contains considerable noise due to the limited length of the time series. We propose an integrated approach for inferring multiple gene networks from time series expression data under varying conditions. To the best of our knowledge, our approach is the first reverse-engineering method that is intended for transcriptomic network comparison between varying conditions. Furthermore, we propose a state-of-the-art parameter estimation method, relevance-weighted recursive elastic net, for providing higher precision and recall than existing reverse-engineering methods. We analyze experimental data of MCF-7 human breast cancer cells stimulated by epidermal growth factor or heregulin with several doses and provide novel biological hypotheses through network comparison. The software NETCOMP is available at http://bonsai.ims.u-tokyo.ac.jp/ approximately shima/NETCOMP/.