ExPlain TM -WAX: causal analysis of gene batteries and identification of key nodes in signal transduction networks

Batteries of genes whose expression is changed in unison through different cellular normal and pathological processes are regulated by very specific class of nuclear proteins - transcription factors (TFs). Activity of TFs is, in turn, governed by signal transduction pathways in response to intracellular and extracellular signals. In cases of diseases, aberrant activity of a few key regulatory molecules in such pathways can lead to a global shift in expression of gene batteries in the cell resulting in a disease phenotype. Novel computational tools are needed for automatic analysis of large collections of gene battery expression data in the context of signal transduction and gene regulatory pathways and for identification of key nodes in disease networks.

We developed an integrated computational system ExPlain^TM (www.biobase.de), for causal interpretation of gene expression data and identification of key signaling molecules whose aberration may lead to diseases. The ExPlain^TM system is based on high quality manually curated databases on gene regulatory mechanisms: TRANSFAC®, TRANSPATH® and ExPlain^TM integrates several algorithms for identification of transcription factor binding sites (Match^TM, F-Match, P-Match) and their function-specific combinations, composite regulatory modules (Composite Module Analyst^TM) with network analysis algorithm, KNA (Key Node Analyst), which is a highly optimized network search engine that analyzes signal transduction networks controlling the activities of the corresponding TFs and seeks for key node molecules responsible for the observed concerted gene expression changes. The key node molecules resemble prospective therapeutic targets or disease biomarkers. In this paper we describe a novel high-throughput workflow automatization system, WAX (Workflow Automat for ExPlain^TM). We applied WAX to the full collection of genes encoding components of the most important canonical cellular pathways. In 50% of the analyzed pathways ExPlain^TM proposed a positive regulatory loops that regulate the activity of these pathways. Key nodes of such feedback circuits can be regarded as “Achilles Heels” of the cells, whose dysfunction frequently causes diseases.