A well-defined set of transcriptional regulatory modules was created and analyzed in the Drosophila embryo.Fractional occupancy-based models were developed to explain the interaction of short range transcriptional repressors with endogenous activators by using quantitative data from these modules.Our fractional occupancy-based modeling uncovered specific quantitative features of short-range repressors; a complex nonlinear quenching relationship, similar quenching efficiencies for different activators, and modest levels of cooperativityThe extension of the study to endogenous enhancers highlighted several features of enhancer architecture design in Drosophila embryos.

Enhancers constitute one of the major components of regulatory machinery of metazoans. Although several genome-wide studies have focused on finding and locating enhancers in the genomes, the fundamental principles governing their internal architecture and cis-regulatory grammar remain elusive. Here, we describe an extensive, quantitative perturbation analysis targeting the dorsal-ventral patterning gene regulatory network (GRN) controlled by Drosophila NF-κB homolog Dorsal. To understand transcription factor interactions on enhancers, we employed an ensemble of mathematical models, testing effects of cooperativity, repression, and factor potency. Models trained on the dataset correctly predict activity of evolutionarily divergent regulatory regions, providing insights into spatial relationships between repressor and activator binding sites. Importantly, the collective predictions of sets of models were effective at novel enhancer identification and characterization. Our study demonstrates how experimental dataset and modeling can be effectively combined to provide quantitative insights into cis-regulatory information on a genome-wide scale.DOI: http://dx.doi.org/10.7554/eLife.08445.001

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