From the known to the unknown: the diverse family of TetR-like regulators in Bacillus subtilis

Although the Gram-positive bacterium Bacillus subtilis is one of the best studied model organisms, there remain many genes and proteins whose functions are unknown. This is also true for many transcriptional regulators that are key to adaptation to changes in the environment. One class of regulators is the group of TetR family of regulators (TFRs). The genome of B. subtilis encodes 20 TFRs, while more than half are poorly characterized. Characterized TFRs of B. subtilis participate in many different aspects of bacterial physiology, ranging from regulation of metabolism, response to plant-derived compounds, detoxification, lifestyle changes, and regulation of septum formation during sporulation. Here, we summarize what is known about the studied regulators and how we can use the knowledge of the characterized TFRs in concert with novel approaches to investigate the function of the poorly characterized regulators. In many cases, gene synteny, meaning the co-conservation of two or more genes together across different species, is a helpful tool to assess functional relationships. Furthermore, structural homologies of the TFRs can hint at similar repressor-ligand interactions and thus also contribute to formulating hypotheses about processes in which they might be involved. Moreover, with the help of innovative tools that predict protein-protein or protein-DNA interactions, we can develop hypotheses about molecular regulatory mechanisms and design experiments based on them. Finally, we discuss some of the more unique TFRs of B. subtilis and propose experiments to elucidate their regulatory functions and the processes they participate in.