Effect of genetic background on the unicellular-to-multicellular epigenetic transition in natural yeast

The unicellular model organism, budding yeast Saccharomyces cerevisiae is also able to grow in a multicellular fashion. The cells can undergo a morphological transition from the typical smooth morphotype to a filamentous/invasive growth type. This process, defined as dimorphism, represents a powerful adaptive mechanism exploited by both pathogenic and not pathogenic fungi [1]. Recent findings revealed the involvement of prion-based epigenetic mechanisms in the generation of complex multicellular phenotypes in yeast [2]. How genetic background influences the prion-driven phenotypic diversity remains a fascinating unsolved question. To address this question we took advantage of a unique system: the natural meiotic segregants of the M28 Saccharomyces cerevisiae isolate, showing high genetic similarity and the 2:2 segregation of the multicellular/unicellular phenotype. Interestingly these strains are able to epigenetically switch from a filamentous to a unicellular phenotype and vice-versa, with a high reversion rate. The treatment of the strains with a low concentration of guanidine hydrochloride (GdHCl), a strong chaotropic agent known to reversibly inhibit prion propagation (Ferreira et al., 2001), significantly decreased the multicellular-to-unicellular transition. Here we applied a multi-level approach, integrating an extensive phenotypic dataset with next generation sequencing data (RNAseq and WGS) and gene expression profiles (Microarray). The gene expression results showed a massive variation accompanying the morphological transition during ethanol growth, with more than 700 genes changing in expression (p-value > 0.05, fold change cut-off 4). In addition, the analysis of protein structural changes through the recent mass spectrometry (MS)-based LiP-SRM technique [3] allowed the identification of several prion-like proteins whose conformation changes during the phenotypic switch, suggesting a multi-faceted regulation of this epigenetic transition. Finally, the integration of transcriptomic, genomic and proteomic data allowed the identification of 10 prion-like proteins as potential regulators of multicellularity in natural yeast. Validations of these candidates are under way together with the investigation of the role of genetic background in misfolded proteins inheritance upon the mophological transition