Integrated signaling pathway and gene expression regulatory model to dissect dynamics of Escherichia coli challenged mammary epithelial cells

Cells transform external stimuli, through the activation of signaling pathways, which in turn activate gene regulatory networks, in gene expression. As more omics data are generated from experiments, eliciting the integrated relationship between the external stimuli, the signaling process in the cell and the subsequent gene expression is a major challenge in systems biology. The complex system of non-linear dynamic protein interactions in signaling pathways and gene networks regulates gene expression. The complexity and non-linear aspects have resulted in the study of the signaling pathway or the gene network regulation in isolation. However, this limits the analysis of the interaction between the two components and the identification of the source of the mechanism differentiating the gene expression profiles. Here, we present a study of a model of the combined signaling pathway and gene network to highlight the importance of integrated modeling. Based on the experimental findings we developed a compartmental model and conducted several simulation experiments. The model simulates the mRNA expression of three different cytokines (RANTES, IL8 and TNFα) regulated by the transcription factor NFκB in mammary epithelial cells challenged with E. coli. The analysis of the gene network regulation identifies a lack of robustness and therefore sensitivity for the transcription factor regulation. However, analysis of the integrated signaling and gene network regulation model reveals distinctly different underlying mechanisms in the signaling pathway responsible for the variation between the three cytokine's mRNA expression levels. Our key findings reveal the importance of integrating the signaling pathway and gene expression dynamics in modeling. Modeling infers valid research questions which need to be verified experimentally and can assist in the design of future biological experiments.

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