Genes Regulated Cooperatively By One or More Transcription Factors and Their Identification in Whole Eukaryotic Genomes

Andreas Wagner The transcription of many eukaryotic genes is regulated via cooperative interactions among transcription factors (TFs). Cooperativity may be homotypic, involving binding of only one transcription factor to multiple sites in a genes' regulatory region. It may also be heterotypic, involving binding of more than one TF. Both types of cooperativity have in common that the binding sites for the respective TFs form tightly linked ``clusters'', groups of binding sites often more closely associated than expected by chance alone. This property can be used to identify genes that are regulated by one or more TFs with known DNA binding specificities. A statistical technique suitable to the identification of statistically significant homotypic or heterotypic TF binding site clusters in whole eukaryotic genomes is presented. The statistical signal of a TF binding site cluster, together with biochemical information about the genes in a cluster's vicinity can be used to identify genes likely to be regulated by the TFs. Application of the technique is illustrated with four transcription factors involved in the cell-cycle and mating control of the yeast Saccharomyces cerevisiae, indicating that the results obtained are biologically meaningful. This rapid and inexpensive computational method of generating hypotheses about gene regulation thus generates information that may be used to guide subsequent costly and laborious experimental approaches. It may aid in the discovery of interactions between genes of known function, as well as in the assignment of biological functions to putative open reading frames. Appears in Bioinformatics15, pp. 776-784.