ExPlain (TM): finding upstream drug targets in disease gene regulatory networks

Different signal transduction pathways leading to the activation of transcription factors (TFs) converge at key molecules that master the regulation of many cellular processes. Such crossroads of signalling networks often appear as Achilles Heels causing a disease when not functioning properly. Novel computational tools are needed for analysis of the gene expression data in the context of signal transduction and gene regulatory pathways and for identification of the key nodes in the networks. An integrated computational system, ExPlain (TM) (www.biobase.de) was developed for causal interpretation of gene expression data and identification of key signalling molecules. The system utilizes data from two databases (TRANSFAC (R) and TRANSPATH (R)) and integrates two programs: (1) Composite Module Analyst (CMA) analyses 5'-upstream regions of co-expressed genes and applies a genetic algorithm to reveal composite modules (CMs) consisting of co-occurring single TF binding sites and composite elements; (2) ArrayAnalyzer (TM) is a fast network search engine that analyses signal transduction networks controlling the activities of the corresponding TFs and seeks key molecules responsible for the observed concerted gene activation. ExPlain (TM) system was applied to microarray data on inflammatory bowel diseases (IBD). The results obtained suggest a number of highly interesting biological hypotheses about molecular mechanisms of pathological genetic disregulation.