We strive to better understand how molecular interactions govern development and differentiation and how they contribute to diseases when they malfunction. Our main research objects are epigenetic multi-protein complexes that are able to chemically modify other proteins and thereby control gene expression and other genetic processes.
Our main questions are: How do chromatin modifying enzymes recognize their target nucleosomes? How does enzymatic regulation locally maximize catalytic activity? How do chromatin modifiers sense the presence or absence of chromatin modifications?
Learn more about chromatin modifications here.
Despite intense research, the complexity of epigenetic regulation is still puzzling and many phenomena remain unexplained. One reason for this is that the activity of chromatin modifiers and effectors is highly context-dependent, and the underlying mechanisms have been difficult to explore. We have two main motivations of addressing this lack of knowledge – we want to elucidate fundamental mechanisms of gene regulation, and understand how dysfunctional epigenetic regulators are driving many types of cancer. As part of the Center for Molecular Medicine Cologne, we are committed to put emphasis on disease-relevant mechanisms and incorporate clinical insights and approaches wherever possible.
Learn more about the CMMC here.
To perform their roles in the cell, epigenetic regulators communicate with one another and with their biochemical chromatin environment through molecular interactions. Using single-particle cryo-electron microscopy (cryo-EM), we are visualizing how such interactions enable the recruitment and local regulation of chromatin modifying enzymes. We use recombinant, purified proteins to reconstitute the activities and interactions of epigenetic factors in vitro. This enables us to address mechanisms of enzymatic regulation in a defined and quantifiable system. Biological function is based on biochemical activity, which in turn is based on the 3D structure and dynamics of proteins and other biomolecules such as DNA and RNA. We therefore combine structural with biochemical and cell biological approaches to address our research questions.
Learn more about cryo-EM, our equipment and infrastructure here.
The processes we are particularly interested in are the methylation and demethylation of lysine residues of histone H3. The methylation status – up to three methyl groups can be added to one lysine – of specific histone residues is linked to distinct genetic outcomes. For example, the methylation of lysine 27 of histone H3 (H3K27me1/2/3) is associated with gene repression. Conversely, acetylation of the same residue (H3K27Ac), in particular in enhancer regions, leads to gene activation. As a consequence, H3K27 has to be de-methylated prior to gene activation. One of our projects is concerned with enzymatic mechanisms of H3K27 demethylation. Other projects in our lab focus on enzymes and complexes that attach and remove the gene activating H3K4 methylation mark and how these regulatory events lead to the concerted up- and downregulation of defined sets of genes.
In collaboration with Prof. Michal-Ruth Schweiger (Structure of the BRD4 stress complex and implications in HPV maintenance and therapy response), we are exploring the molecular composition and epigenetic function of nuclear stress bodies, which are subcellular compartments that are established upon stress conditions such as heat-shock or chemotherapy.
Learn more about our projects here.
Successful science is always embedded in a rich, inspiring and collaborative environment. We are happy to be situated within such an environment here in Cologne. The CMMC, placed on the grounds of the University Clinic of Cologne, is located right next to the Cologne Center for Genomics, the CECAD, the MPI for Ageing Research and the Main Campus of the University.
For more details on our research environment, see here.