Insights into the complex regulatory network acting in yeast cells challenged with drugs/chemical stresses: genome-wide expression approaches supported by bioinformatics

Principal Investigator of the IST team: Isabel Sá-Correia

Contract: PDCT/BIO/56838/2004 - Biochemistry Engineering and Biotechnology

Start date: 01/01/2006

Duration: 24 months


Eight years after disclosure of Saccharomyces cerevisiae genome sequence, this non-pathogenic, easy-to-manipulate eukaryotic experimental model is in a unique position as a tool in biotechnological research, opening the door to the identification of basic biological mechanisms common to all eukaryotes. Yeast cell functions are connected through networks of transcription regulators that may regulate other transcription factors and a large number of other target genes through multiple binding-sites in yeast promoter regions. The complex
effects of drugs/chemical stresses on genomic expression are the direct consequence of the combinatorial regulation of gene expression.
Guided by the massive amount of data emerging from genome-wide expression monitoring it is crucial to elucidate the complex regulatory networks underlying yeast responses to drugs/chemicals, a topic of high relevance in Biotechnology. Indeed, the emergence of resistance to multiple drugs is a major obstacle in the treatment of tumours and infectious diseases. Moreover, the control of resistance of plant pathogens towards plant toxins and fungicides and of food-spoilage fungi to food preservatives, the control of resistance to herbicides and other pesticides and the improvement of resistance to toxic xenobiotics in biodegrading organisms, is of unquestionable importance.
The objective of this project is to unravel the mechanisms ensuring the coordinate transcriptional regulation of yeast genes in response to drugs/chemical stresses by combining the expertise of two research groups: the Biological Sciences Research Group (BSRG), IBQF/IST and the Knowledge Discovery and Bioinformatics Group (KDBIO/ALGOS), INESC-ID. The specific biological problems to be focused during the project include: 1) the regulatory networks underlying yeast responses to: i) two weak acids used either in the food
industry as a preservative (propionic acid) or in agriculture (the herbicide 2,4-D); and ii) three anti-malarial/anti-arrhythmic drugs (quinine, quinidine and artesunate); and 2) the role of the poorly characterized transcriptional regulator Rim101p in yeast response to propionic acid. The massive amounts of data to be analyzed using algorithmical and statistical inference techniques are those recently obtained, and to be obtained during this project, by the BSRG, based on microarray analysis and quantitative proteomics. The promoter sequences of genes found to be co-ordinately expressed under a specific stress agent will be analyzed to identify shared motifs, which may correspond to regulatory elements. Candidate cis-acting elements will be matched against a database of known binding-sites, under construction. This database will be completed, explored and made available to the scientific community during the project. Since co-regulated genes are
frequently involved in a common process, we will try to build gene clusters according to their documented or potential regulation and to infer new interconnections between transcription factors, target genes, metabolic pathways and stress responses.