Transcriptional regulatory networks via gene ontology and expression data

Transcriptional regulatory network (TRN) discovery using information from a single source does not seem feasible due to lack of sufficient information, resulting in the construction of spurious or incomplete TRNs. A methodology, TRND, that integrates a preliminary TRN, gene expression data and gene ontology is developed to discover TRNs. The method is applied to a comprehensive set of expression data on B cell and a preliminary TRN that included 1,335 genes, 443 transcription factors (TFs) and 4032 gene/TF interactions. Predictions were obtained for 443 TFs and 9,589 genes. 14,616 of 4,247,927 possible gene/TF interactions scored higher than the imposed threshold. Results for three TFs, E2F-4, p130 and c-Myc, were examined in more detail to assess the accuracy of the integrated methodology. Although the training sets for E2F-4 and p130 were rather limited, the activities of these two TFs were found to be highly correlated and a large set of coregulated genes is predicted. These predictions were confirmed with published experimental results not used in the training set. A similar test was run for the c-Myc TF using the comprehensive resource www.myccancergene.org. In addition, correlations between expression of genes that encode TFs and TF activities were calculated and showed that the assumption of TF activity correlates with encoding gene expression might be misleading. The constructed B cell TRN, and scores for individual methodologies and the integrated approach are available at systemsbiology.indiana.edu/trndresults.