I am fascinated by the question of how one single cell can develop into many different cell types that ultimately form the organs and tissues of the human body. This is a complex process, which requires different genes to be switched on and off dependent on the cell type. Indeed, genes are regulated at multiple levels, which involve the DNA sequence itself, proteins that bind to DNA and at a higher level the way in which the genome is folded at any given time point, the so-called 3D genome structure. Understanding the basics of gene regulation is paramount if we want to understand what goes wrong when these processes are disrupted in disease, such as developmental disorders or cancer. 

During my PhD studies at the FMI in Basel, Switzerland, I worked with Dirk Schübeler to assess how covalent modifications of DNA are related to the activity of gene regulatory regions. I quickly noticed that if I wanted to investigate all ~20,000 genes and associated hundreds of thousands regulatory regions in the genome, I needed to use computational methods. For my postdoctoral research, I therefore specifically looked for an arrangement that would allow me to expand both my computational and molecular biology skills. Consequently, I applied for a Sir Henry Wellcome Trust Research fellowship to work at the University of Oxford. This fellowship has allowed me to be largely independent at shaping my project and to closely collaborate with scientists from different institutes. I was fortunate to have had great mentors in both Rob Klose (Department of Biochemistry) and Chris Ponting (DPAG). With Chris, I initially developed a bioinformatic data analysis pipeline that then allowed me to quickly progress in my project with Rob. Using mouse embryonic stem cells, I investigate how genome folding is regulated by different proteins and how this relates to switches between gene activation and inactivation. We have identified several unexpected mechanisms that expanded our understanding of how gene regulation is achieved in normal tissues.  

Crucially, it is now evident that genome folding is an integral part of development and is often altered in diseases such as in cancer, suggesting a relevance of our findings for medical research.  

As a basic researcher, I consider myself very fortunate that I have the intellectual freedom to simply follow my curiosity and passion by pursuing the questions that arise along the way.  

However, basic research requires the scientist to constantly be pushing the boundaries of existing knowledge just for the sake of it, without a guarantee that the knowledge acquired will ever be useful to the wider public. Thus, it can sometimes be very hard to justify even to oneself why we are interested in a specific question without an immediate application to it. It very much helps keeping in mind that, as we have seen during the pandemic, fast progress of medical application heavily relies upon a priori conducted basic research. Moreover, advances made in biomedical research often spill over to basic research, allowing for yet more new discoveries and suggesting the two are intimately intertwined. Therefore, since we do not know what may be useful in the future, it is important to push all the boundaries at once, which can be best done by intellectually independent scientists.

Contrary to general expectations, science doesn’t have to be a lonely endeavour. Indeed, it is often at its best when it is conducted in a collaborative, synergistic, manner. Some of my projects benefitted greatly from extreme combination of expertizes, whereas others budded over time to become much more than they seemed to be initially. Most were highly enjoyable, some painful and all highly rewarding. Each of them is special and leaves an imprint in the field. It is thus very hard for me to identify the parts of my research that I am most proud of. I will therefore highlight one of the projects here as an example of the scientific method that I find particularly inspiring. 

Joining Rob’s lab and determined to pursue my interest in the relationship between genome folding and gene activity, I quickly discovered that one of my new colleagues, Emilia Dimitrova, worked on a protein with a high potential to regulate genome folding. At this time, we knew very little about that protein, but hypothesized that it may bookmark inactive genes in embryonic stem cells to be activated in neuronal lineages and that this may involve regulation of genome folding to bring remote neuronal gene regulatory elements close to developmental genes. This would allow developmental genes to become active later on. In the course of our work, it turned out that this hypothesis was only partially true. As initially expected, we identified a new mechanism of genome folding in embryonic stem cells, however the remote elements were different from what we have expected them to be. In fact, only perturbations by CRISPR convinced us that these were indeed gene regulatory elements, suggesting that they behave in an atypical manner. This project is a great demonstration of the scientific method: You may find what you were looking for, but you may be surprised along the way, so it is very important to keep your eyes and mind open.  

Our productive collaboration was an important driver of my research plans for my future independent group and is now extending into a third project.