Refinement and expansion of signaling pathways: the osmotic response network in yeast

The analysis of large-scale genome-wide experiments carries the promise of dramatically broadening our understanding on biological networks. The challenge of systematic integration of experimental results with established biological knowledge on a pathway is still unanswered. Here we present a methodology that attempts to answer this challenge when investigating signaling pathways. We formalize existing qualitative knowledge as a probabilistic model that depicts known interactions between molecules (genes, proteins, etc.) as a network and known regulatory relations as logics. We present algorithms that analyze experimental results (e.g., transcription profiles) vis-à-vis the model and propose improvements to the model based on the fit to the experimental data. These algorithms refine the relations between model components, as well as expand the model to include new components that are regulated by components of the original network. Using our methodology, we have modeled together the knowledge on four established signaling pathways related to osmotic shock response in Saccharomyces cerevisiae. Using over 100 published transcription profiles, our refinement methodology revealed three cross talks in the network. The expansion procedure identified with high confidence large groups of genes that are coregulated by transcription factors from the original network via a common logic. The results reveal a novel delicate repressive effect of the HOG pathway on many transcriptional target genes and suggest an unexpected alternative functional mode of the MAP kinase Hog1. These results demonstrate that, by integrated analysis of data and of well-defined knowledge, one can generate concrete biological hypotheses about signaling cascades and their downstream regulatory programs.