Enhancers, short non-coding DNA sequences known to activate transcription, regulate gene expression by recruiting transcription factors as well as the transcriptional machinery. Recently, Perutz group leader Christa Bücker and her team developed a novel synthetic locus designed to test the activity of one enhancer or combinations of enhancers at defined distances from a promotor. Within their newly funded project, the goal is to expand this approach with a recombination-mediated cassette exchange (RMCE) system. Christa explains: “This approach allows us to fix one enhancer with low activity distal to the promoter. After an exchange with a whole library of enhancers, we investigate in parallel which one of the newly integrated enhancers can now cooperate to upregulate the target promotor.” Systematic testing of a number and combinations of enhancers will hopefully lead to novel insights into the rules and mechanisms that govern gene expression. Among collaborators are the Stark lab (Institute of Molecular Pathology, IMP) that is engaged in building synthetic enhancers, and the Goloborodko lab (Institute of Molecular Biotechnology, IMBA) to model enhancer-promoter interactions within the three-dimensional genome.
Autophagy, the process by which cells recycle damaged or surplus components, requires the identification of cargo, its encapsulation within a newly formed membrane to create the autophagosome, and the targeting of the autophagosome to the lysosome. Aggrephagy – a specific type of autophagy – involves the recycling of aggregated proteins. Since abnormalities in aggrephagy are a hallmark of neurodegenerative diseases, Perutz PI Sascha Martens and his team investigate autophagosome biogenesis in both healthy and pathological cells. "In Alzheimer's disease, Tau protein aggregates are found. While cargo receptors can recognize these pathological aggregates, the autophagosomal response does not proceed as would be expected in healthy cells. Our goal is to uncover the underlying reasons”, Sascha explains. These mechanistic insights and their medical implications in a wide array of neurodegenerative diseases will contribute to a better understanding of health and disease. Sascha and his team collaborate with the Gelpi lab at the Medical University of Vienna, who will provide human brain samples to be analyzed by the Martens lab.