We are interested in understanding how DNA is compacted into chromatin and how epigenetic marks are placed, read and interpreted in this context. Chromatin becomes decorated with post-translational modifications to control the myriad of DNA-related processes in the cell. I will present some of our work in optimising chemical biology approaches that have allowed us to generate the defined reagents required to investigate our biological questions.
For instance, using an optimised chemical ubiquitylation protocol has allowed us to investigate DNA damage repair. We have seen that the exact makeup of both induced and pre-existing epigenetic marks on recombinant chromatin are used as a spatiotemporal marker to define how underlying damaged DNA is repaired.
We have also been applying our protein biochemistry skills to understand how the normally highly conserved histone proteins have diverged extensively in eukaryotes such as Trypanosomatids. Trypanosome infection is responsible for numerous diseases including sleeping sickness and Leishmaniasis in humans. Understanding how the trypanosome genome is organised and responds to stimuli is crucial for our understanding of disease with a large health and economic burden in Africa.
We have reconstituted trypanosome nucleosomes and characterised them using a combination of biochemical and structural biology techniques. I will summarise our exciting results into this with direct implications for chromatin binding and higher order structure of trypanosome chromatin. By identifying common epigenetic mechanisms between trypanosomes and comparing them to better-studied eukaryotic systems we can hope to understand the basic conserved rules of life, and identify new therapeutic opportunities for neglected tropical diseases.
