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.

Optical metabolic imaging quantifies heterogeneous cell populations

“…Tumor heterogeneity may contribute to tumor aggression, invasion, metastases, and therapy resistance [1][2][3]. Studies of tumor heterogeneity are challenging because traditional cell and tissue analyses require pooling of proteins, RNA, or DNA from hundreds to thousands of cells, which provides information on the protein and genetic expression of the majority of cells but may mask unique expression profiles and phenotypes of heterogeneous populations.…”

Fluctuations aléatoires dans le métabolisme et la croissance cellulaires

“…Quantifier les fluctuations à l'échelle de la cellule unique Nous avons combiné microscopie en time-lapse, analyse d'image de cellules uniques, analyse statistique et modé-lisation mathématique pour montrer comment et à quel point les fluctuations d'expression des gènes peuvent affecter la croissance de bactéries Escherichia coli [5]. La microscopie time-lapse consiste simplement à capturer des images de colonies de bactéries à des intervalles de temps réguliers.…”

Quantitative biology: from genes, cells to networks

“…In the third talk of this section, Dr. Sander Tans (FOM Institute AMOLF, Netherlands) showed their recent results in elucidating the role of molecular stochasticity in cellular growth [8]. Using time-lapse microscopy, he demonstrated that expression fluctuations of catabolically active enzymes can propagate and cause growth fluctuations, with transmission depending on the limitation of the enzyme to growth.…”