Dr Nicolai Siegel

SUMMARY

Using the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness, our research aims to elucidate some of the very fundamental and evolutionarily conserved mechanisms of chromatin formation. At the same time we try to understand how changes in chromatin structure can help the parasite to evade the host immune response via antigenic variation. To this end we have established numerous system-wide approaches in T. brucei, including ribosome-profiling, high-resolution ChIP-seq and Hi-C technology as well as a mass spectrometry-based approach to quantify levels of histone acetylation. Using these techniques, we are able to investigate how different chromatin structures are established at specific loci along the genome, how they are formed across the nucleus in 3 dimensions and how they affect gene expression.


INTRODUCTION

The organization of DNA into dense chromatin structures presents an obstacle to the transcriptional machinery. Yet, it also provides an opportunity to regulate gene expression because chromatin structures can be locally and globally modified, making them highly dynamic. Structural changes in chromatin can be induced by the post-translational modification of histones or by the replacement of canonical histones with histone variants. While there is extensive knowledge of the enzymes that add or remove specific histone modifications or replace canonical histones with histone variants, it is not well understood in any organism how these enzymes are targeted to specific genomic loci. Furthermore, it is also not clear how transcriptionally active or repressed chromatin structures are established across the nucleus.

Thus, using trypanosomes to study the formation of chromatin structures, we hope to understand some of the evolutionarily conserved mechanisms of chromatin formation, while at the same time elucidating the role of epigenetic regulation in antigenic variation. Antigenic variation represents the key strategy used by the parasite to evade the host immune response.

Key questions of our research are:

· How are histone variants and histone modifications targeted to specific genomic loci?

· How are chromatin, 3D genome architecture and gene expression linked?

· What role does regulatory ncRNA play in the regulation of gene expression?