The role of DNA-binding specificity in the evolution of bacterial regulatory networks

Understanding the mechanisms by which transcriptional regulatory networks (TRNs) change through evolution is a fundamental problem. Here, we analyze this question using data from Escherichia coli and Bacillus subtilis, and find that paralogy relationships are insufficient to explain the global or local role observed for transcription factors (TFs) within regulatory networks. Our results provide a picture in which DNA-binding specificity, a molecular property that can be measured in different ways, is a predictor of the role of transcription factors. In particular, we observe that global regulators consistently display low levels of binding specificity, while displaying comparatively higher expression values in microarray experiments. In addition, we find a strong negative correlation between binding specificity and the number of co-regulators that help coordinate genetic expression on a genomic scale. A close look at several orthologous TFs, including FNR, a regulator found to be global in E. coli and local in B. subtilis, confirms the diagnostic value of specificity in order to understand their regulatory function, and highlights the importance of evaluating the metabolic and ecological relevance of effectors as another variable in the evolutionary equation of regulatory networks. Finally, a general model is presented that integrates some evolutionary forces and molecular properties, aiming to explain how regulons grow and shrink, as bacteria tune their regulation to increase adaptation.