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Today, it is well-known that in eukaryotic cells the complex interplay of transcription factors (TFs) bound to the DNA of promoters and enhancers is the basis for precise and specific control of transcription. Computational methods have been developed for the identification of potentially cooperating TFs through the co-occurrence of their binding sites (TFBSs). One challenge of these methods is the differentiation of TFBS pairs that are specific for a given sequence set from those that are ubiquitously appearing, rendering the results highly dependent on the choice of a proper background set. Here, we present an extension of our previous PC-TraFF approach that estimates the background co-occurrence of any TF pair by preserving the (oligo-) nucleotide composition and, thus, the core of TFBSs in the sequences of interest. Applying our approach to a simulated data set with implanted TFBS pairs, we could successfully identify them as sequence-set specific under a variety of conditions. When we analyzed the gene expression data sets of five breast cancer associated subtypes, the number of overlapping pairs could be dramatically reduced in comparison to our previous approach. As a result, we could identify potentially cooperating transcriptional regulators that are characteristic for each of the five breast cancer subtypes. This indicates that our approach is able to discriminate specific potential TF cooperations against ubiquitously occurring combinations. The results obtained with our method may help to understand the genetic programs governing specific biological processes such as the development of different tumor types.

Removing Background Co-occurrences of Transcription Factor Binding Sites Greatly Improves the Prediction of Specific Transcription Factor Cooperations