De-Novo Discovery of Differentially Abundant Transcription Factor Binding Sites Including Their Positional Preference

Transcription factors are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in promoters. The de-novo discovery of transcription factor binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not been fully solved yet. Here, we present a de-novo motif discovery tool called Dispom for finding differentially abundant transcription factor binding sites that models existing positional preferences of binding sites and adjusts the length of the motif in the learning process. Evaluating Dispom, we find that its prediction performance is superior to existing tools for de-novo motif discovery for 18 benchmark data sets with planted binding sites, and for a metazoan compendium based on experimental data from micro-array, ChIP-chip, ChIP-DSL, and DamID as well as Gene Ontology data. Finally, we apply Dispom to find binding sites differentially abundant in promoters of auxin-responsive genes extracted from Arabidopsis thaliana microarray data, and we find a motif that can be interpreted as a refined auxin responsive element predominately positioned in the 250-bp region upstream of the transcription start site. Using an independent data set of auxin-responsive genes, we find in genome-wide predictions that the refined motif is more specific for auxin-responsive genes than the canonical auxin-responsive element. In general, Dispom can be used to find differentially abundant motifs in sequences of any origin. However, the positional distribution learned by Dispom is especially beneficial if all sequences are aligned to some anchor point like the transcription start site in case of promoter sequences. We demonstrate that the combination of searching for differentially abundant motifs and inferring a position distribution from the data is beneficial for de-novo motif discovery. Hence, we make the tool freely available as a component of the open-source Java framework Jstacs and as a stand-alone application at http://www.jstacs.de/index.php/Dispom.Author Summary: Binding of transcription factors to promoters of genes, and subsequent enhancement or repression of transcription, is one of the main steps of transcriptional gene regulation. Direct or indirect wet-lab experiments allow the identification of approximate regions potentially bound or regulated by a transcription factor. Subsequently, de-novo motif discovery tools can be used for detecting the precise positions of binding sites. Many traditional tools focus on motifs over-represented in the target regions, which often turn out to be similarly over-represented in the entire genome. In contrast, several recent tools focus on differentially abundant motifs in target regions compared to a control set. As binding sites are often located at some preferred distance to the transcription start site, it is favorable to include this information into de-novo motif discovery. Here, we present Dispom a novel approach for learning differentially abundant motifs and their positional preferences simultaneously, which predicts binding sites with increased accuracy compared to many popular de-novo motif discovery tools. When applying Dispom to promoters of auxin-responsive genes of Arabidopsis thaliana, we find a binding motif slightly different from the canonical auxin-response element, which exhibits a strong positional preference and which is considerably more specific to auxin-responsive genes.