Genome concentration limits cell growth and modulates proteome composition in Escherichia coli

Defining the cellular factors that drive growth rate and proteome composition is essential for understanding and manipulating cellular systems. In bacteria, ribosome concentration is known to be a constraining factor of cell growth rate, while gene concentration is usually assumed not to be limiting. Here, using single-molecule tracking, quantitative single-cell microscopy, and modeling, we show that genome dilution in Escherichia coli cells arrested for DNA replication results in a decrease in the concentration of active RNA polymerases and ribosomes. The resulting sub-linear scaling of total active RNA polymerases and ribosomes with cell size leads to sub-exponential growth, even within physiological cell sizes. Cell growth rate scales proportionally with the total number of active ribosomes in a DNA concentration-dependent manner. Tandem-mass-tag mass spectrometry experiments further reveal that a decrease in DNA-to-cell-volume ratio proportionally remodels the composition of the proteome with cell size independently of the environment. Altogether, our findings indicate that genome concentration is an important driver of exponential cell growth and a global modulator of proteome composition in E. coli . Comparison with studies on eukaryotic cells suggests DNA concentration-dependent scaling principles of gene expression across domains of life.