Gene and genomic regulation: defining complex transcription regulatory networks

Team :   Isabel Sá-Correia, Miguel C Teixeira, Nuno P Mira, Sandra C dos Santos, Paulo J Dias, Catarina Costa, and the PhD students: Sílvia Henriques, Joana Guerreiro


Transcriptional regulation depends on the action of transcription factors (TFs), activators and/or repressors, that bind to specific DNA sequences present in the promoter region of target genes and thereby modulate transcription. At a global scale, the transcript level of a given gene results from the concerted action of these specific TFs, operating in intertwined and complex regulatory networks.


Research Topics

1.   Global analysis of the regulators controlling the adaptive responses and resistance to weak acid stress in yeasts

Two transcriptional regulatory networks, dependent on the transcription factors Haa1p and Rim101p, were recently implicated by our research group in yeast response and resistance to acetic and propionic acids, based on transcriptomic and chemogenomics approaches. Acetic acid and propionic acid are food preservatives and resistance of spoilage yeasts and fungi to these weak acids is a major concern. The role played by the Haa1p signalling pathway in S. cerevisiae response and resistance to these acids is being examined at the proteome and metabolome levels. The identification of an Haa1p-like regulator and signalling pathway in the spoilage yeast Zygosaccharomyces bailii, intrinsically more tolerant to weak acids than S. cerevisiae, is envisaged. Expression proteomics and metabolomics are also being used to elucidate the adaptive response to acetic acid stress in Z. bailliand the role of the Haa1p-like protein in that global response.


2. Understanding transcription factor-DNA interactions based on structural- and nanobiotechnology- based approaches

The transcription factor Haa1 is the main player in reprogramming yeast genomic expression in response to acetic acid stress. Microarray analysis was used to obtain the list of genes whose expression changes in the dependency of Haa1 in response to acetic acid stress. Surface Plasmon Resonance and electrophoretic mobility shift assays were or are being used to identify Haa1 and other transcription factor binding sites. The Haa1-dependent transcriptional regulatory network active in the yeast response to acetic acid stress is being re-evaluated based on the knowledge of Haa1 direct target genes. The development of a nanostructured acoustic wave biosensor for the detection and analysis of transcription factor interactions is also planned, in collaboration with IBB/CBME, University of Algarve.


3. Development and validation of bioinformatics tools to describe complex transcription regulatory networks

Computational tools are being applied to the management and analysis of the massive amount of data emerging from genome-wide expression analyses, in collaboration with the KDBIO Group of INESC-ID, envisioning the delineation of the complex networks underlying yeast responses to chemicals of biomedical and biotechnological relevance. Joint activities in the field of Bioinformatics applied to the understanding of global transcriptional regulatory networks involved the creation and maintenance, updating and upgrading of the YEASTRACT database, as well as the development and application to biological analysis of bi-clustering algorithms for the identification of regulatory modules in time series gene expression data. The development and test of algorithms to model complex transcription regulatory networks, such as that underlying the transcriptional activation, under mancozeb stress, of the multidrug resistance transporter encoded by the FLR1 gene are also among the joint research activities.


Selected Publications

- Teixeira, M.C., Monteiro, P.T., Guerreiro, J.F., Gonçalves, J.P., Mira, N.P., dos Santos, S.C., Cabrito, T., Palma, M., Costa, C., Francisco, A.P., Madeira, S.C., Oliveira, A.L., Freitas, A.T., Sá-Correia, I., The YEASTRACT database: an upgraded information system for the analysis of gene and genomic transcription regulation in Saccharomyces cerevisiae, Nucleic Acids Research, 42: D161-D166, 2014.

- de Carvalho, J., Rodrigues, R.M.M., Tomé, B., Henriques, S.F., Mira, N.P., Sá-Correia, I., Ferreira, G.N.M., "Conformational and Mechanical changes of DNA upon transcription factor binding detected by a QCM and transmission line model", Analyst, 139(8): 1847-55, 2014.

- Mira, N.P., Henriques, S.F., Keller, G., Matos, R., Arraiano, C., Teixeira, M.C., Winge, D.R., Sá-Correia I., "Identification of a DNA-binding site for the transcription factor Haa1, required for Saccharomyces cerevisiae response to acetic acid stress", Nucleic Acids Research , 16: 6896-6907, 2011.

- Gonçalves, J.P., Francisco, A.P., Mira, N.P., Teixeira, M.C. , Sá-Correia, I., Oliveira, A.L. , Madeira, S. "TFRank: Network-based prioritization of regulatory associations underlying transcriptional responses", Bioinformatics , 27, 3149-3157, 2011.

- Mira, N.P., Becker, J.D., Sá-Correia, I. , "Genomic expression program involving the Haa1p-regulon in Saccharomyces cerevisiaeresponse to acetic acid", OMICS: a Journal of Integrative Biology , 14: 587-601, 2010.

- Teixeira, M.C., Dias, P.J., Monteiro, P.T., Sala, A., Oliveira, A.L., Freitas, A.T., Sá-Correia, I. , "Refining current knowledge on the yeast FLR1 regulatory network by combined experimental and computational approaches", Molecular Biosystems , 6: 2471-2481, 2010.

- N.P. Mira, A. Lourenço, A. Fernandes, J. Becker, I. Sa-Correia, The RIM101 pathway has a role in Saccharomyces cerevisiae adaptive response and resistance to propionic acid and other weak acids, FEMS Yeast Research,  9, 202-216, 2009.