The focus of this project is to elucidate the underlying mechanism for lysis/lysogeny decision making in E. coli upon infection by phage lambda, a paradigmatic system for cell-fate determination and developmental genetic networks. This system offers appealing opportunities to examine how the stochasticity of gene expression from a single gene and spatial aspects involved in the process contribute to the stochasticity-determinism duality nature of the decision-making process which involves a regulatory genetic network. Through our recent study using live-cell microscopy, we hypothesized a different and surprising decision-making scenario from the classical picture. However, the underlying mechanism remains unclear. We propose a systematic investigation of this system in much more detail at the single-cell/single-virus/single-molecule level. The proposal has three specific aims.
The first Aim focuses on elucidating how individual phage genome contributes to the lysis/lysogeny decision. It includes exploring how the spatiotemporal information of phage DNA inside the cell correlates with cell fates, how the description of lysis/lysogeny decision in response to the known deterministic factors (e.g. number of infecting phages per cell and cell size) is improved when examined at the single phage-DNA level, and how phages cooperate or compete with each other through mixed infection experiments.
The second Aim focuses on determining the sensitivity and responsiveness of the lysis/lysogeny over a full spectrum of distinct growth conditions and phage factors systematically and investigating the gene expression with high-resolution and high-throughput methods.
The final Aim i s to develop mathematical and computational models of gene expression that account for phage replication, to explain the influence of various genetic and environmental factors on the lysis/lysogeny decision. Overall, our hope is to reach a quantitative understanding of how various deterministic factors and stochasticity contribute to the outcome of a well-known, but incompletely understood developmental process.

Public Health Relevance

This project aims to decipher the underlying mechanism for cell-fate decision making in E. coli upon infection by phage lambda. This study will answer the question how cells process information from the environment, in this case, phage lambda infection, and choose different fates. Our study will impact the understanding of the development of different cell fates, HIV virus in humans, gene copy number variations in health and disease, and provide insights on the antibacterial strategy, phage therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM107597-01A1
Application #
8887426
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lyster, Peter
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$361,981
Indirect Cost
$92,230
Name
Texas A&M Agrilife Research
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843
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Shao, Qiuyan; Trinh, Jimmy T; Zeng, Lanying (2018) High-resolution studies of lysis-lysogeny decision making in bacteriophage lambda. J Biol Chem :
Gordeeva, Julia; Morozova, Natalya; Sierro, Nicolas et al. (2018) BREX system of Escherichia coli distinguishes self from non-self by methylation of a specific DNA site. Nucleic Acids Res :
Shao, Qiuyan; Cortes, Michael G; Trinh, Jimmy T et al. (2018) Coupling of DNA Replication and Negative Feedback Controls Gene Expression for Cell-Fate Decisions. iScience 6:1-12
Guan, Jingwen; Shi, Xu; Burgos, Roberto et al. (2017) Visualization of phage DNA degradation by a type I CRISPR-Cas system at the single-cell level. Quant Biol 5:67-75
Cortes, Michael G; Trinh, Jimmy T; Zeng, Lanying et al. (2017) Late-Arriving Signals Contribute Less to Cell-Fate Decisions. Biophys J 113:2110-2120
Trinh, Jimmy Tri; Zeng, Lanying (2017) Virus interactions: cooperation or competition? Future Microbiol 12:561-564
Trinh, Jimmy T; Székely, Tamás; Shao, Qiuyan et al. (2017) Cell fate decisions emerge as phages cooperate or compete inside their host. Nat Commun 8:14341
Shao, Qiuyan; Trinh, Jimmy T; McIntosh, Colby S et al. (2017) Lysis-lysogeny coexistence: prophage integration during lytic development. Microbiologyopen 6:
Fan, Xiangyu; Duan, Xiangke; Tong, Yan et al. (2016) The Global Reciprocal Reprogramming between Mycobacteriophage SWU1 and Mycobacterium Reveals the Molecular Strategy of Subversion and Promotion of Phage Infection. Front Microbiol 7:41