The Empirical Fluctuation Pattern of E. coli Division Control

Abstract

In physics, it is customary to represent the fluctuations of a stochastic system at steady state in terms of linear response to small random perturbations. Previous work has shown that the same framework describes effectively the trade-off between cell-to-cell variability and correction in the control of cell division of single E. coli cells. However, previous analyses were motivated by specific models and limited to a subset of the measured variables. For example, most analyses neglected the role of growth rate variability. Here, we take a comprehensive approach and consider several sets of available data from both microcolonies and microfluidic devices in different growth conditions. We evaluate all the coupling coefficients between the three main measured variables (interdivision times, cell sizes and individual-cell growth rates). The linear-response framework correctly predicts consistency relations between a priori independent experimental measurements, which confirms its validity. Additionally, the couplings between the cell-specific growth rate and the other variables are typically non zero. Finally, we use the framework to detect signatures of mechanisms in experimental data involving growth rate fluctuations, finding that (1) noise-generating coupling between size and growth rate is a consequence of inter-generation growth rate correlations and (2) the correlation patterns agree with a near-adder model where the added size has a dependence on the single-cell growth rate. Our findings define relevant constraints that any theoretical description should reproduce, and will help future studies aiming to falsify some of the competing models of the cell cycle existing today in the literature.

A G1 Sizer Coordinates Growth and Division in the Mouse Epidermis

“…The faster growth rate in vitro may relate to the predominance of adders. In fact, in E. coli, slower and faster growth rates correspond to sizers and adders, respectively [7,34], and it is possible something similar occurs in mammalian cells.…”

Cell Size Regulation Induces Sustained Oscillations in the Population Growth Rate

“…Since κ has a narrow symmetric distribution around its meanκ [28], its distribution can be estimated as a Gaussian with some variance σ 2 κ . Furthermore, unlike the correlation in the generation times, the correlation between the growth rate of mother and daughter cells can be negligible depending on the organ-ism and the growth condition [2,29] and are ignored in this model. Figure 3 shows the population growth rate, k ≡ d ln(N )/dt, in a simulation of the model described above, where now the growth rate of each cell is independently chosen from a Gaussian distribution with the meanκ = ln(2) and CV of 0.07 (time is measured in the unit of τ = ln(2)/κ).…”

A G1 sizer mechanism coordinates growth and division in the mouse epidermis

“…An alternative explanation for why we observe a sizer in vivo but an adder in vitro is that cells grow more slowly in vivo, with average G1 growth rate being ~5 µm 3 hr -1 in vivo compared to ~80 µm 3 hr -1 for HeLa cells in vitro [10]. A 3-fold change in growth rate clearly impacts size control in E. coli, which exhibit an adder when growing quickly but a sizer when growing more slowly [7,33]. Finally, we note that we have only analyzed skin stem cells and other cell types could have different size control mechanisms in vivo.…”