Abstract

The goal of this project is to develop nano-biotechnologies in order to exploit information obtained from global gene expression studies. The programme will be built on the use of reliable, cheap and re-usable micro/macroarrays for high throughput, low-costs screenings. S. cerevisiae, the only eukaryote for which the complete genome sequence is available and the functions of the genes are being rapidly elucidated will be used to characterise, in detail, regulatory networks on a genome-wide scale. Drawing the integrated genetic and metabolic map of this simple eukaryote will allow biotechnological improvments of many bioprocesses, access to key target genes homolog to human genes involved in diseases and systematic screening of new drugs and fungicides.

Objectives

The Project focuses on the technological development of reasonably priced, reusable, and reproducible hybridisation arrays. We will exploit the enormous potential of the yeast system to characterise the proteins which control its transcriptome and, consequently, its metabolome in order to produce a genetic and metabolic map of this basic eukaryotic cell. The detailed characterisation of regulatory networks on a genome-wide scale will enable the establishment of high throughput, low-cost methods for the screening and validation of new drugs for either medical or veterinary use as well as novel fungicides for plant protection.

Description of the work

The tasks are grouped into six work-packages that, in an integrated and synergistic way, will permit the validation of S. cerevisiae for the identification of new medical and veterinary drugs, as well as novel fungicides.

• Work-package 1 will focus on the technological development of micro/macro-arrays that are sufficiently cheap and reliable for use in industrial screens.
• Work-packages 2 to 5 represent an integrated programme for studying global controls on gene expression. Work-package 2 will study, at the level of both the transcriptome and metabolome, the effects of modification of transcriptional activators on key metabolic pathways. Based on this genomic technology, new ways to modulate biomass or the production of primary and secondary metabolites will be found.
• Workpackage 3 will identify and characterise transactivators involved in the control of cell growth and division. Given that basic regulatory mechanisms are conserved between yeast and humans, the elucidation of these pathways should identify key genes whose products could be useful therapeutic targets.
• Work-package 4 is devoted to studying transactivators of unknown function in order to maximise the chances of identifying novel therapeutic or fungicidal targets.
• Workpackge 5 will focus on the effects of accessory proteins that act as co-activators/repressors of transcription factors and which could be sensitive targets for drug or fungicide action.
• Workpackage 6 will establish basic protocols for drug-screening in yeast for validation and further exploitation of yeast as a model system.

• Technological development of robust micro/macroarrays for monitoring the yeast transcriptome in a reproducible and economic way.
• Identification of transactivators for exploitation in remodelling metabolic pathways to optimise the production of biomass or specific metabolites.
• Elucidation of the effects of yeast transactivators homologous to human proteins involved in diseases.
• Definition of new transactivation pathways.
• Identification of accessory proteins that could be drug targets.
• Establishment of standard protocols and validation of yeast for industrial drug screening.

Contacts

Coordinator

• Université Paris-Sud Institut de Génétique et Microbiologie / FRANCE

Participant

• Roland BEFFA / Aventis CropScience La Dargoire Research centre / FRANCE
• Alain FOURNIER / Aventis Pharma Core Biotechnoloy/Yeast Genomics / FRANCE
• E. DUBOIS / Department of Molecular Biology Institute of Microbiological Research (IRMW) / BELGIUM
• D. MARECHAL / Eurogentec BELGIUM
• B. DUJON / Institut Pasteur FRANCE
• Antony WRIGHT / Södertörns Högskola Section for Natural Sciences / SWEDEN
• Jens NIELSEN / Technical University of Denmark Department of Biotechnology / DENMARK
• Enrique HERRERO / Universitat de Lleida Facultat de Medicina / SPAIN
• Stephen OLIVER / Victoria University of Manchester School of Biologial Sciences / UNITED KINGDOM