Abstract
Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases, for example, for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the codivergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity.
Highlights
Introduction cisRegulatory evolution plays an important role in phenotypic diversity, including morphological (Prud’Homme et al 2006), physiological (Siepel and Arbiza 2014), and behavioral (Wray 2007; Saul et al 2017) evolution
We analyzed Transcription factor (TF) occupancy data for five TFs that form the core of a regulatory network essential for mesoderm development in Drosophila (Wilczynski and Furlong 2010): Twist (Twi), Myocyte enhancer factor-2 (Mef2), Tinman (Tin), Bagpipe (Bap), and Biniou (Bin)
We examined the evolution of DNA accessibility in two distant species and found it to be an important determinant or correlate of interspecies changes in TF binding
Summary
Introduction cisRegulatory evolution plays an important role in phenotypic diversity, including morphological (Prud’Homme et al 2006), physiological (Siepel and Arbiza 2014), and behavioral (Wray 2007; Saul et al 2017) evolution. Many studies have examined cross-species changes in various aspects of gene regulation, including expression (Paris et al.2013), enhancer activity (Khoueiry et al 2017), transcription factor (TF)-DNA binding (Bradley et al 2010; Stefflova et al 2013; Carvunis et al 2015; Wong et al 2015), TF-binding motifs (Moses et al 2006; Bradley et al 2010; He et al 2011; Cheng et al 2014; Naval-Sanchez et al 2015), DNA accessibility (Alexandre et al 2018), and chromatin states (Lesch et al 2016). Evol. 11(1):1813–1828. doi:10.1093/gbe/evz103 Advance Access publication May 22, 2019
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