Transcription Factor Promiscuity Drives Regulatory Rewiring and Evolvability in Gene Networks in Bacteria.

This special issue marking the University of Bath's 60th anniversary offers an opportunity to reflect on nearly a decade of research into the evolution of gene regulatory networks (GRNs) from members of the  lab and elsewhere. Our goal is to understand how GRNs rewire and how new transcription factor (TF) functions evolve. Using an experimental evolution model system with the soil bacterium Pseudomonas fluorescens, we have been able to observe TF rewiring in real time, providing unique insights into the principles of GRN evolution. In this perspective, we highlight three central discoveries from this system: a hierarchical pattern of TF rewiring, in which some regulators act as preferred "first responders"; the critical influence of expression level and mutational accessibility on whether a TF can be recruited for novel function; and the role of crosstalk (non-cognate binding) as the raw material for adaptive innovation. Together, these findings reveal why evolutionary pathways are often constrained and thus strikingly repeatable. By identifying what makes a TF evolvable, we are beginning to predict, and potentially direct, evolutionary outcomes. Finally, we consider open questions and emerging technologies that have the potential to transform our understanding of GRN rewiring and its relationship with evolvability.