Pathway analysis has been extensively applied to aid in the interpretation of the results of genome-wide transcription profiling studies, and has been shown to successfully find associations between the biological phenomena under study and biological pathways. There are two widely used approaches of pathway analysis: over-representation analysis, and gene set analysis. Recently genome-wide transcription factor binding data has become widely available allowing for the application of pathway analysis to this type of data. In this work, we developed regulatory enrichment pathway analysis (REPA) to apply gene set analysis to genome-wide transcription factor binding data to infer associations between transcription factors and biological pathways. We used the transcription factor binding data generated by the ENCODE project, and gene sets from the Molecular Signatures and KEGG databases. Our results showed that 54 percent of the predictions examined have literature support and that REPA's recall is roughly 54 percent. This level of precision is promising as several of REPA's predictions are expected to be novel and can be used to guide new research avenues. In addition, the results of our case studies showed that REPA enhances the interpretation of genome-wide transcription profiling studies by suggesting putative regulators behind the observed transcriptional responses.

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