Journal
JOURNAL OF THE ROYAL SOCIETY INTERFACE
Volume 11, Issue 95, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsif.2014.0140
Keywords
stochastic gene expression; lambda phage; first-passage time; feed-forward circuit; host lysis; stochastic promoter switching
Categories
Funding
- Professional Staff Congress of the City University of New York
- National Science Foundation (Division of Environmental Biology Awards) [0804039, 1148879]
- National Science Foundation (Division of Molecular and Cellular Biosciences Award) [0918199]
- National Science Foundation [DMS-1312926]
- University of Delaware Research Foundation (UDRF)
- Oak Ridge Associated Universities (ORAU)
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1312926] Funding Source: National Science Foundation
- Division Of Environmental Biology
- Direct For Biological Sciences [1148879, 0804039] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0918199] Funding Source: National Science Foundation
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The inherent stochastic nature of biochemical processes can drive differences in gene expression between otherwise identical cells. While cell-to-cell variability in gene expression has received much attention, randomness in timing of events has been less studied. We investigate event timing at the single-cell level in a simple system, the lytic pathway of the bacterial virus phage lambda. In individual cells, lysis occurs on average at 65 min, with an s.d. of 3.5 min. Interestingly, mutations in the lysis protein, holin, alter both the lysis time (LT) mean and variance. In our analysis, LT is formulated as the first-passage time (FPT) for cellular holin levels to cross a critical threshold. Exact analytical formulae for the FPT moments are derived for stochastic gene expression models. These formulae reveal how holin transcription and translation efficiencies independently modulate the LT mean and variation. Analytical expressions for the LT moments are used to evaluate previously published single-cell LT data for lambda phages with mutations in the holin sequence or its promoter. Our results show that stochastic holin expression is sufficient to account for the intercellular LT differences in both wild-type phages, and phage variants where holin transcription and the threshold for lysis have been experimentally altered. Finally, our analysis reveals regulatory motifs that enhance the robustness of lysis timing to cellular noise.
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