Non-Mammalian Models for Systems Biology

London
Friday, 23 June 2006

Non-Mammalian Models for Systems Biology
Friday, 23 June 2006 09:00 - 17:00

Birkbeck College
Room 633
6th Floor
Malet Street
London
WC1E 7HX
United Kingdom

Map and Directions

9:00 - 9:30 Registration

9:30 - 9:35 Introduction by the Chair: Dr Steve Russell, University of Cambridge

9:35 - 10:05 In vivo mapping of transcription factor binding at a genome-wide scale in Drosophila - Dr Steve Russell - University of Cambridge

The ability to develop gene regulatory network models requires an understanding of where in the genome transcription factors are bound and what genes they regulate.  We have developed robust methods for the genome-wide analysis of protein DNA interactions using intact fly tissues that facilitates an better understanding of transcriptional regulation and chromatin organisation in vivo.

10:05-10:35 Systems Biology Approaches to Modelling Transcription Networks in Escherichia coli - Dr Dov Stekel - Lecturer in Bioinformatics, School of Biosciences, University of Birmingham

We will discuss three types of approach to modelling the transcription network of Escherichia coli, which all come under the broad banner of 'Systems Biology'. At one end of the spectrum are data-driven approaches, in which we use computer analyses of microarray to find nonlinear relationships between genes. In the middle are approaches which combine data with theory, in which we construct mathematical models of specific biological systems. At the most abstract end, we use computer simulations of artificial transcription networks to study evolution of such networks. Each of these approaches is illustrated with examples of work from our laboratory.

10:35 -11:00 Morning tea/coffee

11:00 -11:30 Genetics screens in a Drosophila model of Alzheimer¡¦s disease yield novel targets for therapy - Dr Damian Crowther - University of Cambridge

Alzheimer¡¦s disease (AD) is the most common neurodegenerative disease in the world affecting over 15 million people.  The primary disorder is the over-production of an aggregatory peptide called amyloid beta-peptide (Abeta).  We have made a model of AD in the fly by expressing Abeta in the brain.  The fly has histological, behavioural and longevity phenotypes.  We have used the longevity phenotype to perform a genome wide P-element screen and have identified genetic modifiers of Abeta toxicity.

11:30 -12:00 Microarray analysis of the yeast proteome - Dr Paul Bertone, European Bioinformatics Institute, Wellcome Trust Genome Campus Cambridge

This talk will discuss the development of protein-based microarrays for the large-scale characterisation of biochemical activities. Full-length, functional proteins are produced from a library of expression clones, purified as GST::HisX6::fusions and immobilised to various support surfaces at high spatial density. This technology enables high-throughput screening for protein interactions with various analytes and chemical libraries, using procedures analogous to those developed for DNA microarrays. The method was first explored in a pilot study to assay the protein kinases of the budding yeast Saccharomyces cerevisiae using a silicone elastomer microwell array prototype, then extended to the entire yeast proteome using conventional contact-printing microarray technology. This platform is used to assess protein-protein, protein-nucleic acid and small-molecule interactions, enzymatic activity and posttranslational modifications on a proteome-wide scale.

12:00 - 12:30 Xenomics: Functional genomic approaches in Xenopus to investigate the molecular bases of embryonic development, wound healing and tissue regeneration - Professor Enrique Amaya, The Healing Foundation Centre, University of Manchester

12:30 - 13:30 Lunch in the exhibition hall

13:30 -14:00 Global Regulatory Mechanisms of Post-Transcriptional Gene Expression in Fission Yeast  - Dr Jurg Bahler, Wellcome Trust Sanger Institute, Cambridge

Gene expression is regulated at multiple levels, from transcription to translation.  We are studying global roles of translational regulation and its coordination with other layers of post-transcriptional regulation to provide system-wide insight into gene expression control.  Translational profiling provided data on the ribosomes associated with each mRNA.  We then combined this information with genome-wide data on mRNA steady-state levels, mRNA turnover, and poly(A) tail lengths.  This indicated that different mRNA properties influence translation rates at a genome-wide level and that mRNA levels and poly(A) tails are coordinated with translational efficiency.

14:00 -14:30 The Caenorhabditis elegans Transcription Factor Localizome - Dr John S Reece-Hoyes, University of Leeds

The Localization of Expression Mapping Project (LEMP) is using cloned C.elegans promoter fragments to generate a genome-wide set of expression patterns ¡V termed the Localizome. The Localizome will provide essential locational data for validating interactions found by other C.elegans genome-wide assays. The current focus of the LEMP is on transcription factor genes with the view that these data will help reveal transcription regulatory networks and lead to a better understanding of gene expression control in C.elegans, and potentially other organisms as well.

14:30 -15:00   Afternoon tea/coffee

15:00 -15:30 A comparison of theoretical and in vitro studies of iron acquisition in pasteurella multocida - Mr Sandy McDonald, Moredun Research Institute

15:30 -16:00 Initiation of differential gene expression in sporulating Bacillus subtilis ¡V ,a mathematical model - Professor Michael Yudkin, Kellogg College, Oxford, OX1 2JA, United Kingdom

Early in sporulation Bacillus subtilis undergoes an asymmetric division to give two compartments, a smaller prespore and a larger mother cell, which differ in volume by at least five-fold.  Differential gene expression is established in these compartments as a result of the activity of compartment-specific transcription factors called sigma (ƒã) factors.  The first of these is ƒãF, which becomes active in the prespore soon after asymmetric division, partially supplanting the "house-keeping" ƒã factor (ƒãA) which is active before asymmetric septation.  Regulation of ƒãF, which is essential to the success of sporulation, depends on the proteins SpoIIAB (AB), SpoIIAA (AA) and SpoIIE (IIE).  AB is bifunctional: it can act as an anti-sigma factor by binding to ƒãF or as a protein kinase that phosphorylates AA to AA-phosphate.  AA is the substrate of the kinase.  IIE is a protein phosphatase that hydrolyses AA-phosphate back to AA.

In the past several years we and others have identified the reactions in which these proteins are involved, established the kinetic constants associated with them and measured the intracellular concentrations of the proteins.  We have now used these kinetic constants and concentrations to write a set of linked differential equations, which together constitute a mathematical model that describes the regulation of ƒãF.  One of the major predictions of the model is that AB, which is known to be a dimer, is an allosteric protein that binds AA with positive cooperativity.  We have verified this prediction experimentally.

The model has succeeded in showing why the activity of ƒãF appears only after asymmetric septation and why it is confined to the prespore.  It has also succeeded in explaining an observation that had previously appeared paradoxical ¡V that the affinity of ƒãF for the core RNA polymerase is 25-fold lower than that of ƒãA, while its concentration is only two-fold higher.  The model shows that two of the critical features that ensure the correct regulation of ƒãF are the allosteric nature of AB and the difference in volume between the prespore and the mother cell.

16:00 Close

 

 

 

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    Sally Wheatland
    Euroscicon
    PO Box 49717
    London
    N20 8WH.

    Payment must be received prior to the meeting

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