The packaging of our genome into chromatin not only enables the DNA to fit into the eukaryotic nucleus, it also provides a complex platform for multi-layered genome regulation and maintenance. Chromatin modifying enzymes have evolved to keep chromatin flexible and adjustable to the requirements of the cell and are essential regulators for all genomic processes.
The research in our lab aims to elucidate how chromatin modifying events are regulated and integrated, as well as their impact on cellular processes in higher eukaryotes. Furthermore, we study the molecular basis of diseases caused by aberrant regulation of chromatin modifiers.
Chromatin regulation by BAF chromatin remodellers
BRG1- or BRM-associated factor (BAF) complexes are adenosine triphosphate (ATP)-dependent chromatin remodelling enzymes that utilize energy from ATP hydrolysis to eject nucleosomes or slide them along the DNA. This allows parts of the genomic DNA to become either amenable or inaccessible to other factors such as transcription factors and DNA repair enzymes. Consequently, these chromatin remodellers are required for all cellular processes involving the genome.
BAF complexes are comprised of several subunits, which are encoded by more than 30 genes. These subunits assemble in a modular, combinatorial and sometimes cell type-dependent fashion into a large variety of different complexes. Their polymorphic occurrence is further enhanced by post-translational modifications and various transient interaction partners influencing their functions. Three main subgroups with partly distinct biological roles are currently distinguished based on specific incorporated subunits. However, our understanding of the molecular function and regulation of individual subcomplexes and how they integrate with other regulatory mechanisms is still incomplete.
Chromatin remodelling in development and disease
BAF complexes can exert highly specialised control of cellular processes through cell type-specific expression and composition patterns. For example, the composition of BAF complexes changes during neurogenesis, and this is essential for differentiation as well as stage-specific gene expression programs. The importance of BAF complexes is further highlighted by the fact that mutations in BAF subunits can cause (neuro)developmental diseases. Moreover, large-scale genomic sequencing studies have revealed a high frequency of mutations in genes encoding BAF complex subunits across numerous tumour types. Because many BAF complex mutations are associated with various human diseases, unravelling the precise molecular function of BAF complexes and their components will be important to identify disease-specific mechanisms that can be targeted for therapy.
To investigate these fundamental as well as pathogenic mechanisms, we combine model systems such as stem cell differentiation and organoids with state-of-the art experimental and computational techniques, including CRISPR/Cas9 genome editing, targeted protein degradation, (single-cell) genomics, proteomics, imaging, as well as biochemical and molecular biology methods.
If you are interested in joining our team, please contact us via email. We welcome highly motivated experimental and computational scientists at all career stages.