The role of chromatin accessibility in cis-regulatory evolution

Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes iswellrecorded, itsrole in evolutionarydivergence of TFbinding,which inturn 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,forexample,forthemasterregulatorTwistandforearlierdevelopmentalstages,moreaccuratelypredictbinding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion ofthe codivergence of TF pairs.We notedthat accessibility and motif changes offer complementary views ofthe 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.