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Cooperative action in eukaryotic gene regulation: Physical properties of a viral example
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
2007 (English)In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics: Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics, ISSN 1063-651X, E-ISSN 1095-3787, Vol. 76, no 6Article in journal (Refereed) Published
Abstract [en]

The Epstein-Barr virus (EBV) infects more than 90% of the human population, and causes glandular fever as well as several more serious diseases. It is a tumor virus, and has been widely studied as a model system for cell transformation in humans. A central feature of the EBV life cycle is its ability to persist in human B cells in different latency states, denoted latency I, II, and III. In latency III the host cell is driven to cell proliferation and hence expansion of the viral population without entering the lytic pathway, while the latency I state is almost completely dormant. We here study the effective cooperativity of the viral C promoter, active in latency III EBV cell lines. We show that the unusually large number of binding sites of two competing transcription factors, one viral and one from the host, serves to make the switch sharper (higher Hill coefficient), either by cooperative binding between molecules of the same species when they bind, or by competition between the two species if there is sufficient steric hindrance.

Place, publisher, year, edition, pages
2007. Vol. 76, no 6
Keyword [en]
EPSTEIN-BARR-VIRUS, MULTIPLE EBNA1-BINDING SITES, NUCLEAR ANTIGEN-1, TRANSCRIPTIONAL REGULATION, C PROMOTER, DNA, ENHANCER, ORIGIN, REPLICATION, ACTIVATION
National Category
Other Physics Topics Fusion, Plasma and Space Physics
Identifiers
URN: urn:nbn:se:kth:diva-12089DOI: 10.1103/PhysRevE.76.061909ISI: 000251985600071Scopus ID: 2-s2.0-37249031032OAI: oai:DiVA.org:kth-12089DiVA: diva2:301247
Note
2007 Licentiatavhandling Acceppted QC20100720Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2017-12-12Bibliographically 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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