BackgroundIn eukaryotic cells, transcription factors (TFs) are thought to act in a combinatorial way, by competing and collaborating to regulate common target genes. However, several questions remain regarding the conservation of these combinations among different gene classes, regulatory regions and cell types.ResultsWe propose a new approach named TFcoop to infer the TF combinations involved in the binding of a target TF in a particular cell type. TFcoop aims to predict the binding sites of the target TF upon the nucleotide content of the sequences and of the binding affinity of all identified cooperating TFs. The set of cooperating TFs and model parameters are learned from ChIP-seq data of the target TF. We used TFcoop to investigate the TF combinations involved in the binding of 106 TFs on 41 cell types and in four regulatory regions: promoters of mRNAs, lncRNAs and pri-miRNAs, and enhancers. We first assess that TFcoop is accurate and outperforms simple PWM methods for predicting TF binding sites. Next, analysis of the learned models sheds light on important properties of TF combinations in different promoter classes and in enhancers. First, we show that combinations governing TF binding on enhancers are more cell-type specific than that governing binding in promoters. Second, for a given TF and cell type, we observe that TF combinations are different between promoters and enhancers, but similar for promoters of mRNAs, lncRNAs and pri-miRNAs. Analysis of the TFs cooperating with the different targets show over-representation of pioneer TFs and a clear preference for TFs with binding motif composition similar to that of the target. Lastly, our models accurately distinguish promoters associated with specific biological processes.ConclusionsTFcoop appears as an accurate approach for studying TF combinations. Its use on ENCODE and FANTOM data allowed us to discover important properties of human TF combinations in different promoter classes and in enhancers. The R code for learning a TFcoop model and for reproducing the main experiments described in the paper is available in an R Markdown file at address https://gite.lirmm.fr/brehelin/TFcoop.