Regulatory scope shapes the adaptive landscapes of bacterial transcription factor binding sites

Abstract

Transcription factors (TFs) span a regulatory hierarchy from local regulators that control one or few genes to global regulators that regulate hundreds. Local TFs typically operate through few, highly specific binding sites; global TFs through many of varying affinity. Whether this difference in TF biology systematically affects TFBS evolution is unclear. Here, we address this question by studying experimentally mapped adaptive landscapes of transcription factor binding sites (TFBSs) for five bacterial TFs that differ in their regulatory scope -- TetR (local), LasR (semi-global), and CRP, Fis, and IHF (global). All landscapes are rugged and epistatic, but three topographic properties vary systematically with regulatory scope. First, mean mutational robustness increases from local to global TFs. Second, high-regulation-strength peaks are clustered in the local landscape but dispersed in the global ones. Third, adaptive evolution reaches high adaptive peaks more readily in local landscapes. All five landscapes also harbor many evolvability-enhancing (EE) mutations, which increase the likelihood that subsequent mutations are beneficial. The fraction of these mutations is approximately an order of magnitude higher than previously reported for a protein landscape. Populations experiencing EE mutations consistently reach higher regulation strength, an effect that is strongest in the local TetR landscape. Together, these results identify regulatory scope as an organising axis of TFBS adaptive landscapes.