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FR-like EBNA1 binding repeats in the human genome
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
2010 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, 524-529 p.Article in journal (Refereed) Published
Abstract [en]

Epstein Barr Virus (EBV) is widely spread in the human population. EBV nuclear antigen 1 (EBNA1) is a transcription factor that activates viral genes and is necessary for viral replication and partitioning, which binds the EBV genome cooperatively. We identify similar EBNA1 repeat binding sites in the human genome using a nearest-neighbour positional weight matrix. Previously experimentally verified EBNA1 sites in the human genome are successfully recovered by our approach. Most importantly, 40 novel regions are identified in the human genome, constituted of tandemly repeated binding sites for EBNA1. Genes located in vicinity of these regions are presented as possible targets for EBNA1-mediated regulation. Among these, four are discussed in more detail: IQCB1, IMPG1, IRF2BP and TPO. Incorporating the cooperative actions of EBNA1 is essential when identifying regulatory regions in the human genome and we believe the findings presented here are highly valuable for the understanding of EBV-induced phenotypic changes.

Place, publisher, year, edition, pages
2010. Vol. 405, no 2, 524-529 p.
Keyword [en]
EBNA1, Epstein-Barr virus, Family of Repeats, Human binding sites
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:kth:diva-12093DOI: 10.1016/j.virol.2010.06.040ISI: 000281130500028PubMedID: 20655080Scopus ID: 2-s2.0-77955661979OAI: oai:DiVA.org:kth-12093DiVA: diva2:301264
Note
QC 20100720. Updated from submitted to published 20120326Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2017-12-12Bibliographically approved
In thesis
1. 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
2. On diverse biophysical aspects of genetics: from the action of regulators to the characterization of transcripts
Open this publication in new window or tab >>On diverse biophysical aspects of genetics: from the action of regulators to the characterization of transcripts
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genetics is among the most rewarding fields of biology for the theoretically inclined, offering both room and need for modeling approaches in the light of an abundance of experimental data of different kinds. Many aspects of the field are today understood in terms of physical and chemical models, joined by information theoretical descriptions. This thesis discusses different mechanisms and phenomena related to genetics, employing tools from statistical physics along with experimental biomolecular methods. Five articles support this work.

Two articles deal with interactions between proteins and DNA. The first one reports on the properties of non-specific binding of transcription factors proteins in the yeast Saccharomyces cerevisiae, due to an effective background free energy which describes the affinity of a single protein for random locations on DNA. We argue that a background pool of non-specific binding sites is filled up before specific binding sites can be occupied with high probability, thus presenting a natural filter for genetic responses to spurious transcription factor productions. The second article describes an algorithm for the inference of transcription factor binding sites for proteins using a realistic physical model. The functionality of the method is verified on a set of known binding sequences for Escherichia coli transcription factors.

The third article describes a possible genetic feedback mechanism between human cells and the ubiquitous Epstein-Barr virus (EBV). 40 binding regions for the major EBV transcription factor EBNA1 are identified in human DNA. Several of these are located nearby genes of particular relevance in the context of EBV infection and the most interesting ones are discussed.

The fourth article describes results obtained from a positional autocorrelation analysis of the human genome, a simple technique to visualize and classify sequence repeats, constituting large parts of eukaryotic genomes. Applying this analysis to genome sequences in which previously known repeats have been removed gives rise to signals corroborating the existence of yet unclassified repeats of surprisingly long periods.

The fifth article combines computational predictions with a novel molecular biological method based on the rapid amplification of cDNA ends (RACE), coined 5’tagRACE. The first search for non-coding RNAs encoded in the genome of the opportunistic bacterium Enterococcus faecalis is performed here. Applying 5’tagRACE allows us to discover and map 29 novel ncRNAs, 10 putative novelm RNAs and 16 antisense transcriptional organizations.

Further studies, which are not included as articles, on the monitoring of secondary structure formation of nucleic acids during thermal renaturation and the inference of genetic couplings of various kinds from massive gene expression data and computational predictions, are outlined in the central chapters.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. xxii, 98 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2011:04
Keyword
transcription regulation, regulatory motifs, binding affinity, genetic interactions, secondary structure, sequence repeats, transcript characterization
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-31490 (URN)978-91-7415-911-0 (ISBN)
Public defence
2011-04-06, Sal FB53, Roslagstullsbacken 21, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20110316Available from: 2011-03-17 Created: 2011-03-16 Last updated: 2011-03-17Bibliographically approved

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