Modeling binding specificities of transcription factor pairs with random forests

Abstract

Abstract Background Transcription factors (TFs) bind regulatory DNA regions with sequence specificity, form complexes and regulate gene expression. In cooperative TF-TF binding, two transcription factors bind onto a shared DNA binding site as a pair. Previous work has demonstrated pairwise TF-TF-DNA interactions with position weight matrices (PWMs), which may however not sufficiently take into account the complexity and flexibility of pairwise binding. Results We propose two random forest (RF) methods for joint TF-TF binding site prediction: and . We train models with previously published large-scale CAP-SELEX DNA libraries, which comprise DNA sequences enriched for binding of a selected TF pair. builds a random forest with sub-sequences selected from CAP-SELEX DNA reads with previously proposed pairwise PWM. outperforms (area under receiver operating characteristics curve, AUROC, 0.75) the current state-of-the-art method i.e. orientation and spacing specific pairwise PWMs (AUROC 0.59). Thus, may be utilized to improve prediction accuracy for pre-determined binding preferences. However, pairwise TF binding is currently considered flexible; a pair may bind DNA with different orientations and amounts of dinucleotide gaps or overlap between the two motifs. Thus, we developed , which utilizes random forests by considering simultaneously multiple orientations and spacings of the two factors. Our approach outperforms (AUROC 0.78) PWMs, as well as (p<0.00195). provides an approach for predicting TF-TF binding sites without prior knowledge on pairwise binding preferences. However, more research is needed to assess eligibility for practical applications. Conclusions Random forest is well suited for modeling pairwise TF-TF-DNA binding specificities, and provides an improvement to pairwise binding site prediction accuracy.