We investigate proteins that regulate gene expression during differentiation and cellular stress. Focusing on transcription factors and chromatin-associated enzyme complexes, we decipher mechanisms of their activity regulation using biochemical and structural biology approaches.
Chromatin is the dynamic assembly of a cell’s DNA, associated proteins and nucleic acids. We are interested in the mechanisms by which gene regulation is coordinated through regulatory factors within this complex biochemical environment.
Protein interactions and the molecular structure of multi-protein complexes are the key to understanding cellular protein function. Chromatin is at the heart of genome regulation, and we aim to elucidate molecular mechanisms controlling cell fate and stress responses in aging, development and disease.
Transcription factors and chromatin regulators such as histone modifying enzymes function in a complex biochemical environment. Key to their function is the faithful regulation of their enzymatic activities in time and space of the nucleus. These fundamental functional properties are controlled by means of dynamic molecular interactions and post-translational modifications. In our group, we aim to decipher these dynamic interactions as a basis of molecular regulation. This in turn helps us to rationally explain the physiological function of important chromatin regulators and may tell us how their dysfunction contributes to disease processes.
We use engineered cellular systems to identify novel molecular interactions and investigate the function of transcription factors and chromatin regulators in the complex context of a cell. This information is then used to reconstitute defined macromolecular complexes in vitro. Biochemical assays, as well as biophysical and structural biology approaches enable us to visualize and quantify protein-protein interactions and determine their impact on the structure and activity of multi-protein complexes.
Among the latter, we are interested in histone methyltransferases and demethylases that target lysine residues of histone proteins. By changing the biochemical properties of histones, which form the core of nucleosomes, the basic structural unit of chromatin, these enzymes are key players in regulating chromatin structure and function. We have successfully employed single-particle cryo-EM to visualize regulatory interactions of the human epigenetic regulator Polycomb Repressive Complex 2 (PRC2), leading to novel insights into the localized activity of this crucial factor in the genome. We have been successively expanding our tool set to include functional assays, interactomics and further structural methods such as cross-linking mass spectrometry.