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Epstein-Barr virus latency switch in human B-cells: a physico-chemical model
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
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2007 (English)In: BMC SYST BIOL, ISSN 1752-0509, Vol. 1Article in journal (Refereed) Published
Abstract [en]

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, C-P and Q(P), 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 C-P and Q(P) 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.

Place, publisher, year, edition, pages
2007. Vol. 1
Keyword [en]
MULTIPLE EBNA1-BINDING SITES, BURKITTS-LYMPHOMA CELLS, NUCLEAR ANTIGEN 1, TRANSCRIPTION FACTORS, GENE-TRANSCRIPTION, EBNA-1 GENE, C PROMOTER, BINDING-PROTEIN, DNA-BINDING, I LATENCY
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-12078DOI: 10.1186/1752-0509-1-40ISI: 000252362900001Scopus ID: 2-s2.0-37749007113OAI: oai:DiVA.org:kth-12078DiVA: diva2:301059
Note
QC20100720Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2010-07-20Bibliographically approved
In thesis
1. Gene regulation models of viral genetic switches
Open this publication in new window or tab >>Gene regulation models of viral genetic switches
2007 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

The recent decades of research in molecular biology have resulted in break-throughs concerning our knowledge of the genetic code, protein structures and functions of the different cellular components. With this new information follows an increased interest in constructing computational models of the biological systems. A computational model can range from a description of one specific protein to a complete cell or organism. The aim of a computational model is often to complement the experimental studies and help identify essential mechanisms of a system.

All processes taking place in our cells, from general metabolic processes to cell specific actions, originates from information encoded in our DNA. The first step in transferring the genetic information to a functional protein or RNA, is through the transcription of a gene. The transcription process is controlled by cellular proteins binding to DNA regions called promoters. The term "genetic switch", used in the title of this thesis, refers to a specific change in transcription activity, where one or several promoters get activated or silenced.

In this thesis, I present studies of the regulation mechanisms in two different genetic switches. The first is a switch between two central promoters in the Epstein- Barr virus. This human virus is mostly known for causing the ’kissing disease’, but is also coupled to several cancer types. Infected cells can change between a resting and a proliferating phenotype, depending on which viral promoter is active. In order to understand what causes uncontrolled proliferation in tumors, it is important to understand the regulation of these viral promoters. The other switch is present in the phage λ, a bacterial virus. This virus has one specific promoter region, controlling expression of two proteins that determine if the phage will remain silent (lysogenic) in the host cell, or start producing new viral particles (go lytic). For the Epstein- Barr virus we tested, and confirmed, the hypothesis that the regulation of the two central promoters can be obtained by only one viral and one human protein. Further, we studied the cooperative effects on one of the promoters, showing that steric hindrance at the promoter region results in a more effective switching than with only cooperative binding present. For the bacteriophage λ we studied the genetically altered λ- Lac mutants, presented by Little & Atsumi in 2006. We demonstrate that the experimental results cannot, in terms of its equilibria, be explained by the mechanisms generally believed to be in control of the lysogenic/ lytic switch.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. x, 60 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2007:20
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-4528 (URN)978-91-7178-806-1 (ISBN)
Presentation
2007-11-30, RB35, Hus 16, Albanova, Roslagstullsbacken 35, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
QC 20101119Available from: 2007-11-12 Created: 2007-11-12 Last updated: 2010-11-19Bibliographically approved
2. Studies of Cellular Regulatory Mechanisms: from Genetic Switches to Cell Migration
Open this publication in new window or tab >>Studies of Cellular Regulatory Mechanisms: from Genetic Switches to Cell Migration
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cellular behaviour depends ultimately on the transcription of genes. If we know how transcription is controlled we have a better chance of understanding cellular processes. This thesis presents six studies, all concerning cellular regulatory mechanisms. One study is purely experimental and five are computational studies.

A large part of the research concerns the Epstein-Barr virus (EBV). We investigate the latency programme switching of EBV, with an equilibrium statistical mechanics model that describes the transcription activities of two central viral promoters. We demonstrate that this system is bistable and predict promoter activities that correlate well with experimental data. Further we study the switching efficiency of one of the promoters, highlighting how competitive binding of transcription factors generates a more efficient geneticswitch.

The EBV protein EBNA1 is known to affect cellular gene expression. With a dinucleotide position weight matrix we search the complete human genome for regions with multiple EBNA1 binding sites. 40 potential binding regions are identified, with several of particular interest in relation to EBV infections. The final study on EBV is purely experimental, in which we demonstrate an interaction between the Syk kinase and integrin β4. Moreover, we show how reduced levels of these proteins affect migration of epithelial LMP2a positive cells, and hypothesise that these effects are due to the Syk-β4 interaction.

The two remaining studies presented in this thesis concern other cellular systems. Dynamic properties of two different regulatory feedback mechanisms for transport and metabolism of small molecules are investigated. The synergetic effect of adding a regulatory loop is exemplified with the iron metabolism in bacteria. The final project concerns the λ phage. With the equilibrium statistical mechanics method for describing promoter activities we characterise the equilibrium properties of λ mutants and compare with experimental findings. We argue that the observed differences between model and experiment are due to a larger perturbation of the genetic circuit than presumed.

The research presented in this thesis shed light on the properties of several regulatory mechanisms. As computational studies they add perspective to the experimental research in this field and provide new hypothesis for further research.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. xiv, 80 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2010:02
National Category
Fusion, Plasma and Space Physics
Identifiers
urn:nbn:se:kth:diva-12096 (URN)
Public defence
2010-03-18, Sal FB53, Roslagstullsbacken 21, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC20100720Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2010-07-20Bibliographically approved

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