Project 5. Methods for detailed characterization of cellular action of pharmacological compounds

 

Key project members: Raoul Frijters, Wilco Fleuren, Tim Hulsen, Wynand Alkema Sponsor: BioAssist (NBIC) and Schering-Plough

 

Project Goal

Development of methodologies and tools for microarray data analysis, aimed at detailed characterization of the cellular action of pharmacological compounds.

 

Introduction

Microarray experiments generate a vast amount of data and the challenge is to understand the biology behind the regulatory programs that are switched on and off in these experiments. In recent years tools for Gene Ontology (GO) mapping and pathway mapping were developed to facilitate the interpretation of microarray experiment results. The outcome of these tools are based on well established relationships between the genes and biological processes in which they participate. However, the primary literature contains much more information about the functions of genes than is captured in structured vocabularies or canonical pathways. ApproachTo capitalize on the wealth of information that is present in the literature, we developed CoPub [CoPub: a literature-based keyword enrichment tool for microarray data analysis, Frijters et al Nucleic Acids Research - Web Server Issue 2008 (NAR 2008, 1-5)]., a tool that uses information from literature to link human, mouse, and rat genes to biomedical keywords describing biological processes, liver pathologies, pathways, drugs, metabolites and diseases. In total 450.000 keywords were searched in ~15 million Medline abstracts to generate a database in which co-occurrences between genes and biomedical keywords are stored.

 

Results to date

We successfully applied CoPub in a study in which we used gene expression data to reveal the mode of toxicity of a variety of compounds [Literature-based compound profiling: application to toxicogenomics, Frijters et al. Pharmacogenomics, Nov. 2007]. In this study, literature information was used to generate compound specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes.To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with eleven hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat a-specific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. CoPub is a useful addition to existing microarray data analysis tools, because it provides an overview of enriched keywords combined with direct access to abstracts in which the co-occurrences were found, and showed to be a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action. CoPub is hosted by SARA and is made available at http://services.nbic.nl/cgi-bin/copub/CoPub.pl. Development of methodologies and tools for microarray data analysis, aimed at detailed characterization of the cellular action of pharmacological compounds.

 

References 2008

R. Frijters, B. Heupers, P. van Beek, M. Bouwhuis, R. van Schaik, J. de Vlieg, J. Polman, W. Alkema. CoPub: a literature-based keyword enrichment tool for microarray data analysis. Nucleic Acids Res. 36 (Web Server Issue): W406–W410.2007 R. Frijters, S. Verhoeven, W. Alkema, R. van Schaik, J. Polman. Literature-based compound profiling: application to toxicogenomics. Pharmacogenomics, 8 (11): 1521-1534.