A central goal of molecular systems biology is to unravel the mechanisms of eukaryotic transcription regulation, for which yeasts provide the simplest model systems. Since direct observation of these mechanisms is not feasible, they must be reconstructed from measurable characteristics such as nucleosome positions, binding of transcription factors, and transcription rates. Using methods from statistical physics, we construct coarse-grained physical models that facilitate the integration and interpretation of this biological data.

The human body is composed of many different types of cells, which have to be accurately maintained during the lifetime of the person. Failure to maintain cell identity has serious consequences and can result in the development of cancer and other diseases. Gene regulation plays a crucial role in the process of cell specialization in the development of tissues and organs. Many genes are regulated by altering their packaging into chromatin, which involves the folding of DNA, the carrier of genetic information, with other proteins. This packaging is done in a similar way in single cell organisms like yeasts and highly complex organisms such as humans. Our research is focused on basic principles of gene silencing by small molecules similar to DNA. These molecules, called small RNAs, interfere with messenger RNA molecules and prevent the information coming from DNA from being expressed and affecting cell identity. Furthermore, these molecules can also be used for drug design and disease therapy. The silencing process is highly conserved in all animals and plants and a fundamental understanding of this process will help us understand why some cells loose their identity and turn into cancer cells.

The information of a cell, its “genome”, can be likened to the information stored in a library. How this information is used (“gene regulation”) is importantly influenced by its accessibility, e.g., if certain books are open on the desk or packed away in the stacks. We study the basic mechanism of genome packaging in the cell nucleus using unicellular yeasts as model organisms.

Post-transcriptional regulation based on small regulatory RNAs (sRNAs) and RNA-binding proteins proteins is an important layer of gene expression control in both pro- and eukaryotes. In this project, we aim at the identification and functional characterization of protein factors involved in riboregulation in Campylobacter jejuni, the most common cause of bacterial gastroenteritis in humans. This will increase our understanding of post-transcriptional regulation and virulence mechanisms not only in Campylobacter but also in a wider range of pathogens.

The development of a complex organism from a single cell, the response to disease, and the maintenance of cellular life in general require cells to constantly regulate the expression of their genes. The central players in this regulation are specialized activator and repressor proteins that bind to specific locations on the genome which are recognized by their DNA sequences. In our project, we will develop physical models and software to precisely measure and predict the binding of these activator and repressor proteins to sequences in the genome.

Embryonic stem cells proliferate and divide to give rise to all cells in a mammalian organism. In this proposal we want to quantify regulatory mechanisms on the transcriptional level based on time-lapse microscopy of dividing cell with additional fluorescently tagged transcription factors. The goal is to learn a predictor in order to accurately determine the time-point of cellular decision on the single-cell level thus allowing experimentation at the decision event.

Gene regulation is a logistic challenge for widely arborized neurons that need to follow local cues during their outgrowth, maintain regional homeostasis, and quickly respond to synaptic inputs at sites a great distance away from their cell body. Local mRNA storage and protein synthesis have been shown to be important for axonal guidance, synaptogenesis, and synaptic plasticity consistent with hypotheses on quasi-autonomous local protein synthesis in neurons. It has however remained technically challenging to identify the kinetics and function of local mRNA translation and understand the parameters of its regulation. In this project, we thus seek to develop a more efficient genetic method for spatiotemporal regulation of specific mRNA levels. This will be pursued by a combination of protein engineering and live cell imaging. The technique aims at enabling systematic analyses of regulation and function of local protein expression and may find broader applications in tissue engineering and interventional studies.

Alpha-synuclein is a major constituent of Lewy bodies, and these protein clumps are the pathological hallmark of Parkinson Disease (PD). While protein clumps are the end stage of the disease, the early steps of alpha-synuclein toxicity are not clear. We focus on the impaired cross talk between neurons at an early step of PD and investigate which additional genetic factors are involved in alpha-synuclein induced loss of connectivity between nerve cells and result in neuron dysfunction.