Macromolecular Crowding Regulates the Gene Expression Profile by Limiting Diffusion

We seek to elucidate the role of macromolecular crowding in transcription and translation. It is well known that stochasticity in gene expression can lead to differential gene expression and heterogeneity in a cell population. Recent experimental observations by Tan et al. have improved our understanding of the functional role of macromolecular crowding. It can be inferred from their observations that macromolecular crowding can lead to robustness in gene expression, resulting in a more homogeneous cell population. We introduce a spatial stochastic model to provide insight into this process. Our results show that macromolecular crowding reduces noise (as measured by the kurtosis of the mRNA distribution) in a cell population by limiting the diffusion of transcription factors (i.e. removing the unstable intermediate states), and that crowding by large molecules reduces noise more efficiently than crowding by small molecules. Finally, our simulation results provide evidence that the local variation in chromatin density as well as the total volume exclusion of the chromatin in the nucleus can induce a homogenous cell population.Author Summary: The cellular nucleus is packed with macromolecules such as DNAs and proteins, which leaves limited space for other molecules to move around. Recent experimental results by C. Tan et al. have shown that macromolecular crowding can regulate gene expression, resulting in a more homogenous cell population. We introduce a computational model to uncover the mechanism by which macromolecular crowding functions. Our results suggest that macromolecular crowding limits the diffusion of the transcription factors and attenuates the transcriptional bursting, which leads to a more homogenous cell population. Regulation of gene expression noise by macromolecules depends on the size of the crowders, i.e. larger macromolecules can reduce the noise more effectively than smaller macromolecules. We also demonstrate that local variation of chromatin density can affect the noise of gene expression. This shows the importance of the chromatin structure in gene expression regulation.