Single-cell growth rate fluctuations contribute independently from protein production to gene expression noise and decrease with average growth rate

Phenotypic heterogeneity is a universal feature in microbial life and has profound consequences for the behavior of single cells. However, dissecting and quantifying the sources of phenotypic noise is challenging as it requires precise quantification of the dynamics of gene expression fluctuations in vivo. Here, we analyze time-lapse microscopy data of single E. coli cells carrying fluorescent reporters for constitutive and ribosomal promoters to quantify how fluctuations in protein production, growth rate, and random sampling at division contribute to noise in protein concentrations. We find that growth rate fluctuations are largely uncorrelated with protein production and contribute substantially to noise in protein concentrations. In addition, as nutrients are varied, growth rate fluctuations decrease both in amplitude and duration with the mean growth rate. In contrast, fluctuations in production do not show a systematic dependence on mean growth rate, but exhibit surprisingly variable behaviors, even across different constitutive promoters. Moreover, although production and growth rate fluctuations are only weakly correlated, they exhibit complex cross-correlation patterns with growth rate that are both condition-and promoter-dependent. These observations suggest that, while growth rate fluctuations might be dominated by a single underlying mechanism, there are multiple sources of protein production fluctuations that vary in strength across conditions and affect different promoters to different extents. Finally, the sampling noise of proteins at cell division only contributes substantially to protein concentration noise for low-expressed genes with ten or fewer molecules per cell.