Macromolecular Crowding Effects on Gene Regulation

Abstract

Studies of macromolecular crowding have shown its important effects on molecular transport and interactions in living cells. Less clear is the effect of crowding when its influence is incorporated into a complex network of interactions. Here we explore the effects of crowding on a model of gene transcription as a network of reactions involving transcription factors, RNA polymerases, and DNA binding sites for these proteins. The novelty of our approach is that we determine the effects of crowding on the rates of these reactions using Brownian Dynamics and Monte Carlo simulations, allowing us to integrate molecular-scale information, such as the shapes and sizes of each molecular species, into the rate equations of the model.The steady state cytoplasmic mRNA concentration shows several regimes with qualitatively different dependencies on the volume fraction ∃∴phi∃ of crowding agents, depending on the concentrations of the transcription factors, polymerases, and DNA binding sites. At physiologically realistic volume fractions, the mRNA output may be an increasing, decreasing, or non-monotonic function of ∃∴phi∃ in these various regimes. Our results suggest that the transcriptional output of a gene can be regulated jointly by the local level of macromolecular crowding, together with the local concentrations of polymerases and DNA-binding proteins.