Regulation of gene expression in eukaryotic genomes is established through a complex cooperative activity of proximal promoters and distant regulatory elements (REs) such as enhancers, repressors, and silencers. We developed a web server called DiRE, from Distant Regulatory Elements, based on the Enhancer Identification (EI) method, to determine the chromosomal location and functional characteristics of distant REs in higher eukaryotic genomes. The server uses gene co-expression data, comparative genomics, and combinatorics of transcription factor binding sites (TFBSs) to find TFBS-association signatures that can be used for discriminating specific regulatory functions. DiRE's unique feature is the detection of REs outside of proximal promoter regions, as it takes advantage of the full gene locus to conduct the search. DiRE can predict common REs for any set of input genes for which the user has prior knowledge of co-expression, co-function, or other biologically meaningful grouping. The server predicts function-specific REs consisting of clusters of specifically-associated TFBSs, and it also scores the association of individual TFs with the biological function shared by the group of input genes. Its integration with the Array2BIO server allows users to start their analysis with raw microarray expression data.
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