title: Stochasticity of metabolism and growth at the single-cell level.
abstract: Elucidating the role of molecular stochasticity in cellular growth is central to understanding phenotypic heterogeneity and the stability of cellular proliferation. The inherent stochasticity of metabolic reaction events should have negligible effect, because of averaging over the many reaction events contributing to growth. Indeed, metabolism and growth are often considered to be constant for fixed conditions. Stochastic fluctuations in the expression level of metabolic enzymes could produce variations in the reactions they catalyse. However, whether such molecular fluctuations can affect growth is unclear, given the various stabilizing regulatory mechanisms, the slow adjustment of key cellular components such as ribosomes, and the secretion and buffering of excess metabolites. Here we use time-lapse microscopy to measure fluctuations in the instantaneous growth rate of single cells of Escherichia coli, and quantify time-resolved cross-correlations with the expression of lac genes and enzymes in central metabolism. We show that expression fluctuations of catabolically active enzymes can propagate and cause growth fluctuations, with transmission depending on the limitation of the enzyme to growth. Conversely, growth fluctuations propagate back to perturb expression. Accordingly, enzymes were found to transmit noise to other unrelated genes via growth. Homeostasis is promoted by a noise-cancelling mechanism that exploits fluctuations in the dilution of proteins by cell-volume expansion. The results indicate that molecular noise is propagated not only by regulatory proteins but also by metabolic reactions. They also suggest that cellular metabolism is inherently stochastic, and a generic source of phenotypic heterogeneity.
authors.affiliation: 1] FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands [2] Department of Environmental Systems Science, ETH Zurich, Universitaetsstrasse 16, 8092 Zurich, Switzerland [3] Department of Environmental Microbiology, Eawag, Ueberlandstrasse 133, 8600 Duebendorf, Switzerland [4].
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kiviet
authors.affiliation: 1] FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands [2] Laboratoire de Biochimie, UMR 8231 CNRS/ESPCI, École Supérieure de Physique et de Chimie industrielles, 10 rue Vauquelin, 75005 Paris, France. [3].
authors.forename: Philippe
authors.initials: P
authors.lastname: Nghe
authors.affiliation: FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands.
authors.forename: Noreen
authors.initials: N
authors.lastname: Walker
authors.affiliation: FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Boulineau
authors.affiliation: FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands.
authors.forename: Vanda
authors.initials: V
authors.lastname: Sunderlikova
authors.affiliation: FOM institute AMOLF, Science Park 104, 1098 XG Amsterdam, the Netherlands.
authors.forename: Sander J
authors.initials: SJ
authors.lastname: Tans
mesh_terms: D049108:Cell Enlargement; D049109:Cell Proliferation; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007763:Lac Operon / Q000235:genetics; D008853:Microscopy; D008954:Models, Biological; D059010:Single-Cell Analysis; D013269:Stochastic Processes; D059008:Time-Lapse Imaging
chemical_list: D029968:Escherichia coli Proteins