E. coli transcription factors regulate promoter activity by a universal, homeostatic mechanism

Transcription factors (TFs) may activate or repress gene expression through an interplay of different mechanisms, including RNA polymerase (RNAP) recruitment, exclusion, and initiation. However, depending on the regulated promoter identity, TF function can vary, and the principles underlying this context dependence remain unclear. We demonstrate an inverse scaling relationship between the promoter's basal activity and its regulation by a given TF. Specifically, activation is weaker and repression is stronger on stronger promoters. This scaling applies to both activators and repressors, which suggests a common underlying mechanism where TFs regulate expression by stabilizing RNAP binding at the promoter. The consequence of this relationship is that TFs buffer expression by affecting constant regulated expression levels across promoters of different basal activity, ensuring homeostatic control despite genetic or environmental changes.