Abstract
Cell fate determination is usually described as the result of the stochastic dynamics of gene regulatory networks (GRNs) reaching one of multiple steady-states each of which corresponds to a specific decision. However, the fate of a cell is determined in finite time suggesting the importance of transient dynamics in cellular decision making. Here we consider cellular decision making as resulting from first passage processes of regulatory proteins and examine the effect of transient dynamics within the initial lysis-lysogeny switch of phage λ. Importantly, the fate of an infected cell depends, in part, on the number of coinfecting phages. Using a quantitative model of the phage λ GRN, we find that changes in the likelihood of lysis and lysogeny can be driven by changes in phage co-infection number regardless of whether or not there exists steady-state bistability within the GRN. Furthermore, two GRNs which yield qualitatively distinct steady state behaviors as a function of phage infection number can show similar transient responses, sufficient for alternative cell fate determination. We compare our model results to a recent experimental study of cell fate determination in single cell assays of multiply infected bacteria. Whereas the experimental study proposed a “quasi-independent” hypothesis for cell fate determination consistent with an observed data collapse, we demonstrate that observed cell fate results are compatible with an alternative form of data collapse consistent with a partial gene dosage compensation mechanism. We show that including partial gene dosage compensation at the mRNA level in our stochastic model of fate determination leads to the same data collapse observed in the single cell study. Our findings elucidate the importance of transient gene regulatory dynamics in fate determination, and present a novel alternative hypothesis to explain single-cell level heterogeneity within the phage λ lysis-lysogeny decision switch.
Highlights
Biochemical pathways and feedbacks in gene regulatory networks (GRNs) shape when and how much genes are expressed
Alternative fate determination is usually described as the result of the inherent bistability of gene regulatory networks (GRNs)
The fate of a cell is determined in finite time suggesting the importance of transient dynamics to cellular decision making
Summary
Biochemical pathways and feedbacks in gene regulatory networks (GRNs) shape when and how much genes are expressed. Differential gene expression can lead to qualitative changes in cellular phenotypes, whether via alternative cell fate determination in unicellular organisms (e.g., competence [1], sporulation [2], persistence [3], and infected cell fate [4]) or via cell differentiation in multi-cellular organisms (e.g., lineage determination [5]). The steps leading to qualitative changes in phenotype are not strictly deterministic. Genetically identical cells can have marked differences in the state of regulatory molecules even when faced with identical environmental conditions [9,10,11]. Determination of cell fate is usually described as the result of the interplay between noise and deterministic dynamics of GRNs which determines the relative frequency of each decision [12,14]
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