Isogenic cells show a large degree of variability in growth rate, even when cultured in the same environment. Such cell-to-cell variability in growth can alter sensitivity to antibiotics, chemotherapy and environmental stress. To characterize transcriptional differences associated with this variability, we have developed a method--FitFlow--that enables the sorting of subpopulations by growth rate. The slow-growing subpopulation shows a transcriptional stress response, but, more surprisingly, these cells have reduced RNA polymerase fidelity and exhibit a DNA damage response. As DNA damage is often caused by oxidative stress, we test the addition of an antioxidant, and find that it reduces the size of the slow-growing population. More generally, we find a significantly altered transcriptome in the slow-growing subpopulation that only partially resembles that of cells growing slowly due to environmental and culture conditions. Slow-growing cells upregulate transposons and express more chromosomal, viral and plasmid-borne transcripts, and thus explore a larger genotypic--and so phenotypic--space.

This work was supported by grants to B.L. from the European Research Council Consolidator Grant (IR-DC 616434), Spanish Ministry of Economy and Competitiveness (BFU2011-26206), the AXA Research Fund, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), and the EMBL-CRG Systems Biology Program. This work was supported by grants to L.B.C. from the department and the AGAUR program (2014 SGR 0974). R.D. acknowledges support from Swiss National Science Foundation through Early Postdoc Mobility Fellowship. D.v.D. was supported by an NWO Rubicon fellowship (825.14.016).