Individuality and slow dynamics in bacterial growth homeostasis

Microbial growth and division are fundamental processes relevant to many areas of life science. Of particular interest are homeostasis mechanisms, which buffer growth and division from accumulating fluctuations over multiple cycles. These mechanisms operate within single cells, possibly extending over several division cycles. However, all experimental studies to date have relied on measurements pooled from many distinct cells. Here, we disentangle long-term measured traces of individual cells from one another, revealing subtle differences between temporal and pooled statistics. By analyzing correlations along up to hundreds of generations, we find that the parameter describing effective cell-size homeostasis strength varies significantly among cells. At the same time, we find an invariant cell size which acts as an attractor to all individual traces, albeit with different effective attractive forces. Despite the common attractor, each cell maintains a distinct average size over its finite lifetime with suppressed temporal fluctuations around it, and equilibration to the global average size is surprisingly slow (> 150 cell cycles). To demonstrate a possible source of variable homeostasis strength, we construct a mathematical model relying on intracellular interactions, which integrates measured properties of cell size with those of highly expressed proteins. Effective homeostasis strength is then influenced by interactions and by noise levels, and generally varies among cells. A predictable and measurable consequence of variable homeostasis strength appears as distinct oscillatory patterns in cell size and protein content over many generations. We discuss the implications of our results to understanding mechanisms controlling division in single cells and their characteristic timescalesComment: In press with PNAS. 50 pages, including supplementary informatio

The roles of intergeneration inheritance and intrageneration molecular dynamics in shaping living cells

We study two important dynamical processes in the bacterium E. coli. The first focuses on understanding how the inheritance of non-genetic components influences cellular properties and restrict heterogeneity in future generations. Heterogeneity in physical and functional characteristics of cells proliferates within an isogenic population due to stochasticity in intracellular biochemical processes and in the distribution of resources during divisions. Conversely, it is limited in part by the inheritance of cellular components between consecutive generations. The aim of this study is to characterize the dynamics of non-genetic inheritance in the simple model organism E. coli, and how it contributes to restraining the variability of various cellular properties. We describe the design of a novel microfluidic device that can trap sister cells in the same environment for 10s of generations. We introduce a new method for measuring proliferation of heterogeneity in bacterial cell characteristics, based on measuring how two sister cells become different from each other over time. Our measurements provide the inheritance dynamics of different cellular properties, and the ‘inertia’ of cells to maintain these properties along time. We find that inheritance dynamics are property specific and can exhibit long-term memory (∼10 generations) that works to restrain variation among cells. Our results can reveal mechanisms of non-genetic inheritance in bacteria and help understand how cells control their properties and heterogeneity within isogenic cell populations. In the second study, we turn our attention to the specific question of cell size control in bacteria and focus on the role of the Min proteins dynamics in determining cell size. We demonstrate that the Min proteins, known to exhibit pole-to-pole oscillation responsible for localizing the septal ring to mid-cell in E. coli, play a crucial role in setting the cell size. We show that manipulating the concentrations ratio of the Min proteins in the cell destabilizes their oscillation temporarily and leads to a delay in the formation of the division ring until the cell reaches a size that would stabilize the oscillation again. As a result, cells divide at a new stable size which is longer than observed in earlier cell-cycles with the preceding concentrations

Multigenerational memory in bacterial size control

Cells maintain a stable size as they grow and divide. Inspired by the available experimental data, most proposed models for size homeostasis assume size control mechanisms that act on a timescale of one generation. Such mechanisms lead to short-lived autocorrelations in size fluctuations that decay within less than two generations. However, recent evidence from comparing sister lineages suggests that correlations in size fluctuations can persist for many generations. Here we develop a minimal model that explains these seemingly contradictory results. Our model proposes that different environments result in different control parameters, leading to distinct inheritance patterns. Multigenerational memory is revealed in constant environments but obscured when averaging over many different environments. Inferring the parameters of our model from bacterial size data in microfluidic experiments, we recapitulate observed statistics of homeostasis and phenotypic inheritance. Our work elucidates the impact of the environment on cell homeostasis and growth and division dynamics.Comment: 17 pages, 8 figure

Bacterial cell-size changes resulting from altering the relative expression of Min proteins

Abstract The timing of cell division, and thus cell size in bacteria, is determined in part by the accumulation dynamics of the protein FtsZ, which forms the septal ring. FtsZ localization depends on membrane-associated Min proteins, which inhibit FtsZ binding to the cell pole membrane. Changes in the relative concentrations of Min proteins can disrupt FtsZ binding to the membrane, which in turn can delay cell division until a certain cell size is reached, in which the dynamics of Min proteins frees the cell membrane long enough to allow FtsZ ring formation. Here, we study the effect of Min proteins relative expression on the dynamics of FtsZ ring formation and cell size in individual Escherichia coli bacteria. Upon inducing overexpression of minE, cell size increases gradually to a new steady-state value. Concurrently, the time required to initiate FtsZ ring formation grows as the size approaches the new steady-state, at which point the ring formation initiates as early as before induction. These results highlight the contribution of Min proteins to cell size control, which may be partially responsible for the size fluctuations observed in bacterial populations, and may clarify how the size difference acquired during asymmetric cell division is offset