Abstract
Combinatorial interplay among transcription factors (TFs) is an important mechanism by which transcriptional regulatory specificity is achieved. However, despite the increasing number of TFs for which either binding specificities or genome-wide occupancy data are known, knowledge about cooperativity between TFs remains limited. To address this, we developed a computational framework for predicting genome-wide co-binding between TFs (CCAT, Combinatorial Code Analysis Tool), and applied it to Drosophila melanogaster to uncover cooperativity among TFs during embryo development. Using publicly available TF binding specificity data and DNaseI chromatin accessibility data, we first predicted genome-wide binding sites for 324 TFs across five stages of D. melanogaster embryo development. We then applied CCAT in each of these developmental stages, and identified from 19 to 58 pairs of TFs in each stage whose predicted binding sites are significantly co-localized. We found that nearby binding sites for pairs of TFs predicted to cooperate were enriched in regions bound in relevant ChIP experiments, and were more evolutionarily conserved than other pairs. Further, we found that TFs tend to be co-localized with other TFs in a dynamic manner across developmental stages. All generated data as well as source code for our front-to-end pipeline are available at http://cat.princeton.edu.
Highlights
Transcriptional regulation controls a diverse range of biological processes, from development to response to external stimuli [1,2]
Recent progress in profiling the binding landscape of transcription factors (TFs) has revealed that a single TF can bind thousands or tens of thousands of regions in a genome [3,4,5], and it is clear that the binding of a single TF cannot achieve the complex and precise control of gene expression exhibited in organisms [6]
We develop a computational pipeline CCAT (Combinatorial Code Analysis Tool) to uncover combinatorially interacting motif pairs, which is designed to overcome difficulties in previous studies, including the requirement for ChIP data sets for the condition of interest or limited searching within promoter regions
Summary
Transcriptional regulation controls a diverse range of biological processes, from development to response to external stimuli [1,2]. The yeast TF MCM1 interacts with several cofactor TFs to combinatorially regulate cell cycle and mating [11,22]. Its binding motif is found near those of its cofactor TFs in many regulons and in several yeast species [22]. Another example comes from the Drosophila TF dl, which works with the TF twist. Binding sites for dl and twist are observed close to each other in the enhancer regions of several genes and across several Drosophila species [20,21], and binding motifs for other TFs, including Su(H), co-locate with them [24]
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