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Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

Werner M, Ernberg I, Zou J, Almqvist J, Aurell E - BMC Syst Biol (2007)

Bottom Line: Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs.We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns.Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Biological Physics, School of Computer Science and Communication, Royal Institute of Technology, AlbaNova University Center, SE-106 91 Stockholm, Sweden. mariawer@kth.se

ABSTRACT

Background: The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs.

Results: Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results.

Conclusion: We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable behavior and a considerable difference in transition dynamics, based on program stability and promoter activities. Both these phenomena we hope can be further investigated experimentally, to increase the understanding of this important switch. Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

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Potential landscape. The potential landscape of the EBV kinetic system for three different levels of Oct-2+Grg/TLE. The two local minima in the potential landscape corresponds to latency I, at low EBNA-1 levels, and latency III, at high EBNA-1 levels. Increasing the Oct-2 levels in the system shift the latency III minima towards latency I and eventually it disappear completely, leaving the system in a monostable latency I state.
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Figure 3: Potential landscape. The potential landscape of the EBV kinetic system for three different levels of Oct-2+Grg/TLE. The two local minima in the potential landscape corresponds to latency I, at low EBNA-1 levels, and latency III, at high EBNA-1 levels. Increasing the Oct-2 levels in the system shift the latency III minima towards latency I and eventually it disappear completely, leaving the system in a monostable latency I state.

Mentions: Our model displays regions of mono-stability, with either latency I or III as the only stable state, and a region of bi-stability. For low Oct-2+Grg/TLE levels, only latency III is stable, while, for higher levels, there is a bistable region. This eventually gives way to the monostable latency I, at even higher Oct-2+Grg/TLE levels. The net effects of production from the two promoters together with dilution and decay can conveniently be visualized by a production potential. The negative derivative of this potential, with respect to the number of EBNA-1, correspond to the net production rate of EBNA-1. Figure 3 displays this production potential for three different levels of Oct-2+Grg/TLE. At intermediate Oct-2+Grg/TLE levels, the system is bistable, i.e. the production potential has two local minima (dashed line). Increasing the Oct-2+Grg/TLE level eventually eliminates latency III (dotted line), while decreasing Oct-2+Grg/TLE level eliminates latency I (solid line).


Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

Werner M, Ernberg I, Zou J, Almqvist J, Aurell E - BMC Syst Biol (2007)

Potential landscape. The potential landscape of the EBV kinetic system for three different levels of Oct-2+Grg/TLE. The two local minima in the potential landscape corresponds to latency I, at low EBNA-1 levels, and latency III, at high EBNA-1 levels. Increasing the Oct-2 levels in the system shift the latency III minima towards latency I and eventually it disappear completely, leaving the system in a monostable latency I state.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2164963&req=5

Figure 3: Potential landscape. The potential landscape of the EBV kinetic system for three different levels of Oct-2+Grg/TLE. The two local minima in the potential landscape corresponds to latency I, at low EBNA-1 levels, and latency III, at high EBNA-1 levels. Increasing the Oct-2 levels in the system shift the latency III minima towards latency I and eventually it disappear completely, leaving the system in a monostable latency I state.
Mentions: Our model displays regions of mono-stability, with either latency I or III as the only stable state, and a region of bi-stability. For low Oct-2+Grg/TLE levels, only latency III is stable, while, for higher levels, there is a bistable region. This eventually gives way to the monostable latency I, at even higher Oct-2+Grg/TLE levels. The net effects of production from the two promoters together with dilution and decay can conveniently be visualized by a production potential. The negative derivative of this potential, with respect to the number of EBNA-1, correspond to the net production rate of EBNA-1. Figure 3 displays this production potential for three different levels of Oct-2+Grg/TLE. At intermediate Oct-2+Grg/TLE levels, the system is bistable, i.e. the production potential has two local minima (dashed line). Increasing the Oct-2+Grg/TLE level eventually eliminates latency III (dotted line), while decreasing Oct-2+Grg/TLE level eliminates latency I (solid line).

Bottom Line: Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs.We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns.Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Biological Physics, School of Computer Science and Communication, Royal Institute of Technology, AlbaNova University Center, SE-106 91 Stockholm, Sweden. mariawer@kth.se

ABSTRACT

Background: The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs.

Results: Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results.

Conclusion: We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable behavior and a considerable difference in transition dynamics, based on program stability and promoter activities. Both these phenomena we hope can be further investigated experimentally, to increase the understanding of this important switch. Our results also stress the importance of the little known regulation of human transcription factor Oct-2.

Show MeSH
Related in: MedlinePlus