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A Novel Computational Approach for the Prediction of Networked Transcription Factors of Aryl Hydrocarbon-Receptor-Regulated Genes

BIOBASE GmbH, Wolfenbüttel, Germany (A.K., V.M., E.W.); Institute of Cytology and Genetics, Novosibirsk, Russia (A.K.); Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, Hannover, Germany (S.R., J.B.); National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (P.N.); and Center of Pharmacology and Toxicology, Medical School of Hannover, Hannover, Germany (J.B.)

A novel computational method based on a genetic algorithm was developed to study composite structure of promoters of coexpressed genes. Our method enabled an identification of combinations of multiple transcription factor binding sites regulating the concerted expression of genes. In this article, we study genes whose expression is regulated by a ligand-activated transcription factor, aryl hydrocarbon receptor (AhR), that mediates responses to a variety of toxins. AhR-mediated change in expression of AhR target genes was measured by oligonucleotide microarrays and by reverse transcription-polymerase chain reaction in human and rat hepatocytes. Promoters and long-distance regulatory regions (>10 kb) of AhR-responsive genes were analyzed by the genetic algorithm and a variety of other computational methods. Rules were established on the local oligonucleotide context in the flanks of the AhR binding sites, on the occurrence of clusters of AhR recognition elements, and on the presence in the promoters of specific combinations of multiple binding sites for the transcription factors cooperating in the AhR regulatory network. Our rules were applied to search for yet unknown Ah-receptor target genes. Experimental evidence is presented to demonstrate high fidelity of this novel in silico approach.

Address correspondence to: Prof. Dr. Jürgen Borlak, Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany. E-mail: borlak{at}item.fraunhofer.de

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