Abstract
AP-1 proteins are transcription factors (TFs) that belong to the basic leucine zipper family, one of the largest families of TFs in eukaryotic cells. Despite high homology between their DNA binding domains, these proteins are able to recognize diverse DNA motifs. In yeasts, these motifs are referred as YRE (Yap Response Element) and are either seven (YRE-Overlap) or eight (YRE-Adjacent) base pair long. It has been proposed that the AP-1 DNA binding motif preference relies on a single change in the amino acid sequence of the yeast AP-1 TFs (an arginine in the YRE-O binding factors being replaced by a lysine in the YRE-A binding Yaps). We developed a computational approach to infer condition-specific transcriptional modules associated to the orthologous AP-1 protein Yap1p, Cgap1p and Cap1p, in three yeast species: the model yeast Saccharomyces cerevisiae and two pathogenic species Candida glabrata and Candida albicans. Exploitation of these modules in terms of predictions of the protein/DNA regulatory interactions changed our vision of AP-1 protein evolution. Cis-regulatory motif analyses revealed the presence of a conserved adenine in 5′ position of the canonical YRE sites. While Yap1p, Cgap1p and Cap1p shared a remarkably low number of target genes, an impressive conservation was observed in the YRE sequences identified by Yap1p and Cap1p. In Candida glabrata, we found that Cgap1p, unlike Yap1p and Cap1p, recognizes YRE-O and YRE-A motifs. These findings were supported by structural data available for the transcription factor Pap1p (Schizosaccharomyces pombe). Thus, whereas arginine and lysine substitutions in Cgap1p and Yap1p proteins were reported as responsible for a specific YRE-O or YRE-A preference, our analyses rather suggest that the ancestral yeast AP-1 protein could recognize both YRE-O and YRE-A motifs and that the arginine/lysine exchange is not the only determinant of the specialization of modern Yaps for one motif or another.
Highlights
Studies of the evolution of transcriptional regulatory networks, which control all phenotypic features, critically depend on the ability to accurately characterize and compare transcriptional modules (TMs) in several different related species
We designed an integrative framework (Figure 1) to identify the sets of genes for which transcription was activated by Yap1p, Cgap1p and Cap1p in response to a specific physiological stimulation, i.e. cell treatment by the antifungal drug benomyl
We used published microarray datasets quantifying the transcriptome responses of the yeasts S. cerevisiae, C. glabrata and C. albicans to similar doses of benomyl for similar time periods [16,21]
Summary
Studies of the evolution of transcriptional regulatory networks, which control all phenotypic features, critically depend on the ability to accurately characterize and compare transcriptional modules (TMs) in several different related species. Protein/DNA interaction data obtained using ChIP-chip or ChIP-seq technologies allow the identification of the set of genes whose promoter sequences directly bind a particular TF in vivo [8] In this context, an optimal approach is to combine several types of experimental data for the same TF in different species. Multiple biological data sources and bioinformatics methodologies were combined using an integrative procedure whose objective was to minimize the risk to select false positive genes in the final TMs. Second, as one TF could control different sets of genes depending on the cell state or the environmental conditions, we used only data obtained in a specific experimental condition, identical in all the species examined. We applied this rationale to the analysis of AP-1 proteins in three different yeasts: the model yeast Saccharomyces cerevisiae (S. cerevisiae) and two pathogenic species Candida glabrata (C. glabrata) and Candida albicans (C. albicans)
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