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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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Promoter activity. The probability of transcription from both promoters, Cp (blue) and Qp (red) as function of EBNA-1 and Oct-2 proteins in the system. This plot shows the case when Oct-2+Grg/TLE has the maximum binding affinity to FR, KdOFR = 2.5 nM. The Qp activity is remarkably low for most EBNA-1 levels compared with the Cp activity.
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Figure 4: Promoter activity. The probability of transcription from both promoters, Cp (blue) and Qp (red) as function of EBNA-1 and Oct-2 proteins in the system. This plot shows the case when Oct-2+Grg/TLE has the maximum binding affinity to FR, KdOFR = 2.5 nM. The Qp activity is remarkably low for most EBNA-1 levels compared with the Cp activity.

Mentions: Figure 4 shows computed Cp and Qp activity in our model, as functions of EBNA-1 and Oct-2+Grg/TLE levels, demonstrating the remarkably different activity levels of the two promoters. The Cp activity (blue surface) is 60–100% of maximum for all Oct-2+Grg/TLE and EBNA-1 levels shown. The Qp activity (red surface) is mostly around 1%, except at very low EBNA-1 levels. Since the half-life of EBNA-1 is long (see Methods), we expect Qp to only be active at a low level in latency I. Our model indeed shows very low Qp activity in latency I, both in the mono and bistable regions. It estimates the Qp activity to be about 1% of its full capacity in latency I, and close to zero in latency III. Cp on the contrary is active at 40–100% of maximum transcription rate in latency III, with the lower activity in the bistable region. In monostable latency I, the Cp activity is essentially zero and below 1% active for latency I in the bistable region. The Cp transcription is strongly dependent on Oct-2+Grg/TLE levels. However, at the system volumes tested here, Oct-2+Grg/TLE levels do not greatly affect Qp activity. To summarize, the two promoters are mutually exclusive in the monostable regions, although their activity levels differ, and also for the latency III state in the bistable region. In the latency I state in the bistable region, the Cp and Qp activities are somewhat comparable. Table 2 summarizes the Cp and Qp transcription activities presented above.


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)

Promoter activity. The probability of transcription from both promoters, Cp (blue) and Qp (red) as function of EBNA-1 and Oct-2 proteins in the system. This plot shows the case when Oct-2+Grg/TLE has the maximum binding affinity to FR, KdOFR = 2.5 nM. The Qp activity is remarkably low for most EBNA-1 levels compared with the Cp activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Promoter activity. The probability of transcription from both promoters, Cp (blue) and Qp (red) as function of EBNA-1 and Oct-2 proteins in the system. This plot shows the case when Oct-2+Grg/TLE has the maximum binding affinity to FR, KdOFR = 2.5 nM. The Qp activity is remarkably low for most EBNA-1 levels compared with the Cp activity.
Mentions: Figure 4 shows computed Cp and Qp activity in our model, as functions of EBNA-1 and Oct-2+Grg/TLE levels, demonstrating the remarkably different activity levels of the two promoters. The Cp activity (blue surface) is 60–100% of maximum for all Oct-2+Grg/TLE and EBNA-1 levels shown. The Qp activity (red surface) is mostly around 1%, except at very low EBNA-1 levels. Since the half-life of EBNA-1 is long (see Methods), we expect Qp to only be active at a low level in latency I. Our model indeed shows very low Qp activity in latency I, both in the mono and bistable regions. It estimates the Qp activity to be about 1% of its full capacity in latency I, and close to zero in latency III. Cp on the contrary is active at 40–100% of maximum transcription rate in latency III, with the lower activity in the bistable region. In monostable latency I, the Cp activity is essentially zero and below 1% active for latency I in the bistable region. The Cp transcription is strongly dependent on Oct-2+Grg/TLE levels. However, at the system volumes tested here, Oct-2+Grg/TLE levels do not greatly affect Qp activity. To summarize, the two promoters are mutually exclusive in the monostable regions, although their activity levels differ, and also for the latency III state in the bistable region. In the latency I state in the bistable region, the Cp and Qp activities are somewhat comparable. Table 2 summarizes the Cp and Qp transcription activities presented above.

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