Details Matter: Noise and Model Structure Set the Relationship between Cell Size and Cell Cycle Timing

Abstract

Organisms across all domains of life regulate the size of their cells. However, the means by which this is done is poorly understood. We study two abstracted “molecular” models for size regulation: inhibitor dilution and initiator accumulation. We apply the models to two settings: bacteria like Escherichia coli, that grow fully before they set a division plane and divide into two equally sized cells, and cells that form a bud early in the cell division cycle, confine new growth to that bud, and divide at the connection between that bud and the mother cell, like the budding yeast Saccharomyces cerevisiae. In budding cells, delaying cell division until buds reach the same size as their mother leads to very weak size control, with average cell size and standard deviation of cell size increasing over time and saturating up to 100-fold higher than those values for cells that divide when the bud is still substantially smaller than its mother. In budding yeast, both inhibitor dilution or initiator accumulation models are consistent with the observation that the daughters of diploid cells add a constant volume before they divide. This “adder” behavior has also been observed in bacteria. We find that in bacteria an inhibitor dilution model produces adder correlations that are not robust to noise in the timing of DNA replication initiation or in the timing from initiation of DNA replication to cell division (the C+D period). In contrast, in bacteria an initiator accumulation model yields robust adder correlations in the regime where noise in the timing of DNA replication initiation is much greater than noise in the C + D period, as reported previously (Ho and Amir, 2015). In bacteria, division into two equally sized cells does not broaden the size distribution.

Cell size regulation in budding yeast does not depend on linear accumulation of Whi5

“…A range of different hypotheses for how cell size could regulate this genetic network have been proposed. We highlight two paradigms of size control: inhibitor dilution or activator accumulation (37,38). Recent observations support an inhibitor dilution model enacted through Whi5, wherein the growth-mediated dilution of Whi5 relative to a roughly constant concentration of Cln3 during G1 increases the rate of passage through Start as cells grow larger (12,39).…”

Modeling Cell Size Regulation: From Single-Cell-Level Statistics to Molecular Mechanisms and Population-Level Effects

“…Analysis and simulations of the initiation-centric model of Eqs. [34][35] show that it produces emergent adder correlations at division [13,40], as long as the magnitude of the fluctuations in the coordination between initiation and division is much less than that in the control of initiation (σ t σ T ). This is indeed the case in experiments for fast-growing bacteria, although the picture appears different for slow-growing bacteria [21], which we discuss later.…”

“…While experiments have suggested that the upstream control occurs over initiation of DNA replication rather than cell division in various microorganisms [6,9,25,39], we first review a simpler model where the accumulation of initiators triggers cell division. The model leads to the adder correlations observed in several species of bacteria and other microorganisms [13,20,40].…”

Bridging the gap between single-cell migration and collective dynamics

“…We here employ the first method. We assume that individual cells grow exponentially [16] over a well-defined period T g . Additional variability in cell cycle length can be achieved by introducing an additional refractory phase with exponentially distributed waiting times and the average waiting time T r , which we set to T r = 0 in this work.…”