TREMOR—a tool for retrieving transcriptional modules by incorporating motif covariance

A transcriptional module (TM) is a collection of transcription factors (TF) that as a group, co-regulate multiple, functionally related genes. The task of identifying TMs poses an important biological challenge. Since TFs belong to evolutionarily and structurally related families, TF family members often bind to similar DNA motifs and can confound sequence-based approaches to TM identification. A previous approach to TM detection addresses this issue by pre-selecting a single representative from each TF family. One problem with this approach is that closely related transcription factors can still target sufficiently distinct genes in a biologically meaningful way, and thus, pre-selecting a single family representative may in principle miss certain TMs. Here we report a method—TREMOR (Transcriptional Regulatory Module Retriever). This method uses the Mahalanobis distance to assess the validity of a TM and automatically incorporates the inter-TF binding similarity without resorting to pre-selecting family representatives. The application of TREMOR on human muscle-specific, liver-specific and cell-cycle-related genes reveals TFs and TMs that were validated from literature and also reveals additional related genes.