Ripamonti, A.; Lacassin, M.; Droghetti, R.; Bokinsky, G.; Cosentino Lagomarsino, M.

Cells regulate gene expression by balancing transcriptional resources across different functional groups of genes. In bacteria, second messengers such as ppGpp and cAMP control ribosome biogenesis and metabolic gene expression, respectively. While these regulators are typically studied in isolation, we provide a theory showing that their effects are intertwined due to global transcriptional competition. Using experimental data from RelA overexpression and a mechanistic modeling framework, we show that ppGpp-mediated repression of ribosomal genes competes for transcriptional resources with cAMP-driven activation of metabolic genes. This competition reshapes proteome allocation in a way that transcends individual regulators. Our findings challenge classic assumptions about transcription factor action and suggest that large-scale gene regulation should be studied within the broader context of resource availability, with implications for understanding cellular regulation across diverse biological systems, beyond bacterial physiology.