Integrating network motifs into a genetic network: A case of study based on the Phop/PhoQ two-component system

Genetic and genomic approaches have been successfully employed to assign genes to distinct regulatory networks. The strength of the connections in these networks must be specified to define the kinetics of a group of genes, but the uncertainty concerning the connections between genes, the ambiguity inherent to the biological processes, and the impossibility of experimentally determining the underlying biological properties only allow a rough prediction of gene interaction. Here we describe a framework that examines promoter sequences and identifies those cis-acting features that define transcriptional network motifs. Then, we employ an iterative process, based on Ordinary Differential Equations, to learn a network architecture that appropriately integrates these motifs into a full structure. The application of this method to the two component systems PhoP/PhoQ and the PmrA/PmrB in Salmonella enterica uncovered novel mechanisms that enable the inter-connection of these networks. The predictions were experimentally verified.