Molecular mechanisms of transcriptional regulation and epigenetics
Previous and current research
Our group is interested in molecular mechanisms of transcriptional regulation in eukaryotes, where DNA is packaged into chromatin. In the context of chromatin, we are interested how different sequence-specific transcription factors assemble on DNA and how sequence-specific transcription factors interact with co-activators and general transcription factors to recruit RNA polymerases to the transcription start site.We are also studying the overall structure, architecture and inner workings of large molecular machines like RNA polymerases or remodelling factors involved in the transcription process. Finally, we aim to gain insight into how DNA sequence information and epigenetic modifications act together to regulate gene transcription.
Figure: Crystal structure of the first bromodomain of Brdt that cooperatively recognises two acetylated lysine residues. During spermatogenesis binding of hyper-acetylated histone tails to Brdt causes chromatin inside the nucleus to compact and clump together (stained blue inside the nuclei of two cells in the background image).
To achieve these goals, we use structural information obtained by X-ray crystallography and electron microscopy combined with other biophysical and biochemical techniques. Systems currently under investigation include transcription factor/DNA complexes, yeast RNA polymerase III and multi-protein complexes involved in chromatin targeting, remodelling and histone modifications.
The accessibility of chromatin in eukaryotes is regulated by ATP-dependent chromatin remodelling factors and histone-modifying enzymes. Both classes of enzymes use similar domains like bromodomains, chromodomains, MBT domains, PHD fingers and SANT domains for the controlled access to defined genomic regions. We try to understand the molecular architecture of chromatin modifying and remodelling complexes, by which mechanisms they are recruited, how they interact with chromatin templates and how their activities are regulated.
RNA polymerase III consists of 17 subunits and is responsible for the transcription of small RNAs like tRNA and 5S RNA. Recruitment of the enzyme requires binding of the general transcription factor TFIIIC, composed of six subunits, to internal promoter sites followed by the binding of TFIIIB composed of three subunits. Our research aims to understand the overall architecture of RNA polymerase III, TFIIIC and TFIIIB and their interactions during the RNA polymerase III recruitment process, transcriptional elongation and termination.
Future projects and goals
Molecular insights into the recruitment of transcriptional regulator through the combination of DNA sequence-specific recognition and epigenetic modifications.
Structural and functional analysis of macromolecular machines involved in transcription, chromatin remodelling and chromatin modification.
Contributing to a better mechanistic understanding of eukaryotic transcription and epigenetics using cell biology, biochemical and structural biology approaches.