Title
To lyse or not to lyse: transient-mediated stochastic fate determination in cells infected by bacteriophages.
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 lambda. Importantly, the fate of an infected cell depends, in part, on the number of coinfecting phages. Using a quantitative model of the phage lambda 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 lambda lysislysogeny decision switch.
Year
DOI
Venue
2011
10.1371/journal.pcbi.1002006
PLOS COMPUTATIONAL BIOLOGY
Keywords
DocType
Volume
dosage compensation,cell fate,transient response,steady state,stochastic model,gene regulatory network
Journal
7
Issue
ISSN
Citations 
3
1553-734X
4
PageRank 
References 
Authors
1.09
0
2
Name
Order
Citations
PageRank
Richard I. Joh141.09
Joshua S. Weitz241.09