Abstract
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.
Highlights
Expressed genes in metazoans are regulated by diverse cis-regulatory elements, including distally-acting sequences termed enhancers (Levine, 2010; Smith and Shilatifard, 2014; Heinz et al, 2015)
High-throughput studies have dramatically increased our knowledge of genome-wide transcription factor occupancy and transcript expression, we have a limited ability to interpret the functional relevance of quantitative aspects of protein binding or DNA sequence variation
Our study indicates that the arrangement and quality of transcription factor binding sites contains an essential common ’grammar’ of cis-regulatory regions that is shared across distinct regulatory elements; this stands in contrast to recent studies suggesting that in some cases transcription factors may recognize their target sequences primarily through protein-protein rather than protein-DNA interactions (Kulkarni and Arnosti, 2005; Junion et al, 2012)
Summary
Expressed genes in metazoans are regulated by diverse cis-regulatory elements, including distally-acting sequences termed enhancers (Levine, 2010; Smith and Shilatifard, 2014; Heinz et al, 2015). Some enhancers show little evolutionary variation, and permit no change in transcription factor binding sites without catastrophic effects on function (Thanos and Maniatis, 1995; Kim and Maniatis, 1997). Demonstrate a more flexible deployment of binding sites, functionally conserved elements can exhibit a large degree of evolutionary variation (Junion et al, 2012). A quantitative understanding of the internal enhancer grammar of cis-regulatory elements will provide researchers with powerful tools to better understand the
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