DiRE: identifying distant regulatory elements of co-expressed genes

Abstract

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 have developed a web server named DiRE, based on the Enhancer Identification (EI) method, for predicting distant regulatory elements in higher eukaryotic genomes, namely for determining their chromosomal location and functional characteristics. The server uses gene co-expression data, comparative genomics and profiles of transcription factor binding sites (TFBSs) to determine TFBS-association signatures that can be used for discriminating specific regulatory functions. DiRE's unique feature is its ability to detect 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 transcription factors (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. The DiRE web server is freely available at http://dire.dcode.org.

Figure 1.

Example of a summary output generated by the DiRE server, publicly available at http://dire.dcode.org/?id=example. The request ID is normally a 16-digit number that replaces ‘example’ in this figure. While visually comprehensive, the output provides easy access to the detailed description (chromosomal location, score, TF content) of candidate REs, to the graphical representation of their genomic distribution and to the list of most important TFs. The ‘occurrence’ represents the fraction of putative REs that contain a particular TFBS, while the ‘importance’ is defined as the product of the TF occurrence and its weight. For users’ convenience links to the original gene lists are provided, as well as to the results of their mapping onto the corresponding genome.

Figure 2.

Logos of the binding sites of the three most frequent TFs associated with the MyoD knockout. Note the common CAgcTG core binding motif. Logos were created with WebLogo (53).