A quantitative model for the transcriptional landscape of the bacterial cell cycle

Regulation of gene activity during the cell cycle is fundamental to bacterial replication but is challenging to study in unperturbed, asynchronous bacterial populations. Using single cell RNA-sequencing of heterogeneous Staphylococcus aureus populations, we uncovered a global gene expression pattern dominated by chromosomal position. We show that this pattern results from the effect of DNA replication on gene expression, and in Escherichia coli, changes under different growth rates and modes of replication. By constructing a quantitative model in each species that links replication to cell cycle gene expression, we identified divergent genes that may be instead subject to distinct regulation, and applied this cell cycle framework to characterize heterogeneity in responses to antibiotic stress. Our approach reveals a highly dynamic cell cycle transcriptional landscape and may be broadly applicable across species. Overall design: scRNA-seq by the PETRI-seq method was performed on bacteria of species Escherichia coli and Staphylococcus aureus. scRNA-seq by the PETRI-seq method was performed on bacteria of species Escherichia coli and Bacillus subtilis.