Computational discovery of transcriptional regulatory rules

MOTIVATION Even in a simple organism like yeast Saccharomyces cerevisiae, transcription is an extremely complex process. The expression of sets of genes can be turned on or off by the binding of specific transcription factors to the promoter regions of genes. Experimental and computational approaches have been proposed to establish mappings of DNA-binding locations of transcription factors. However, although location data obtained from experimental methods are noisy owing to imperfections in the measuring methods, computational approaches suffer from over-prediction problems owing to the short length of the sequence motifs bound by the transcription factors. Also, these interactions are usually environment-dependent: many regulators only bind to the promoter region of genes under specific environmental conditions. Even more, the presence of regulators at a promoter region indicates binding but not necessarily function: the regulator may act positively, negatively or not act at all. Therefore, identifying true and functional interactions between transcription factors and genes in specific environment conditions and describing the relationship between them are still open problems. RESULTS We developed a method that combines expression data with genomic location information to discover (1) relevant transcription factors from the set of potential transcription factors of a target gene; and (2) the relationship between the expression behavior of a target gene and that of its relevant transcription factors. Our method is based on rule induction, a machine learning technique that can efficiently deal with noisy domains. When applied to genomic location data with a confidence criterion relaxed to P-value = 0.005, and three different expression datasets of yeast S.cerevisiae, we obtained a set of regulatory rules describing the relationship between the expression behavior of a specific target gene and that of its relevant transcription factors. The resulting rules provide strong evidence of true positive gene-regulator interactions, as well as of protein-protein interactions that could serve to identify transcription complexes. AVAILABILITY Supplementary files are available from http://www.jaist.ac.jp/~h-pham/regulatory-rules