A Model for Sigma Factor Competition in Bacterial Cells

Abstract

Sigma factors control global switches of the genetic expression program in bacteria. Different sigma factors compete for binding to a limited pool of RNA polymerase (RNAP) core enzymes, providing a mechanism for cross-talk between genes or gene classes via the sharing of expression machinery. To analyze the contribution of sigma factor competition to global changes in gene expression, we develop a theoretical model that describes binding between sigma factors and core RNAP, transcription, non-specific binding to DNA and the modulation of the availability of the molecular components. The model is validated by comparison with in vitro competition experiments, with which excellent agreement is found. Transcription is affected via the modulation of the concentrations of the different types of holoenzymes, so saturated promoters are only weakly affected by sigma factor competition. However, in case of overlapping promoters or promoters recognized by two types of sigma factors, we find that even saturated promoters are strongly affected. Active transcription effectively lowers the affinity between the sigma factor driving it and the core RNAP, resulting in complex cross-talk effects. Sigma factor competition is not strongly affected by non-specific binding of core RNAPs, sigma factors and holoenzymes to DNA. Finally, we analyze the role of increased core RNAP availability upon the shut-down of ribosomal RNA transcription during the stringent response. We find that passive up-regulation of alternative sigma-dependent transcription is not only possible, but also displays hypersensitivity based on the sigma factor competition. Our theoretical analysis thus provides support for a significant role of passive control during that global switch of the gene expression program.

Author Summary

Bacteria respond to changing environmental conditions by switching the global pattern of expressed genes. A key mechanism for global switches of the transcriptional program depends on alternative sigma factors that bind the RNA polymerase core enzyme and direct it towards the appropriate stress response genes. Competition of different sigma factors for a limited amount of RNA polymerase is believed to play a central role in this global switch. Here, a theoretical approach is used towards a quantitative understanding of sigma factor competition and its effects on gene expression. The model is used to quantitatively describe in vitro competition assays and to address the question of indirect or passive control in the stringent response upon amino acids starvation. We show that sigma factor competition provides a mechanism for a passive up-regulation of the stress specific sigma-driven genes due to the increased availability of RNA polymerase in the stringent response. Moreover, we find that active separation of sigma factor from the RNA polymerase during early transcript elongation weakens the sigma factor-RNA polymerase equilibrium constant, raising the question of how their in vitro measure is relevant in the cell.