Decoding mechanisms of gene regulation in African trypanosomes

Trypanosomes are divergent eukaryotic parasites and excellent models for investigating the diversity of gene regulatory mechanisms, including allelic exclusion, histone modification and post-transcriptional control. The variant surface glycoproteins (VSGs) are major virulence determinants and have provided starting-points for decoding regulatory mechanisms. I propose to build upon the following discoveries from my laboratory; - A VSG allelic exclusion machinery that associates with the single active VSG and silences all other alleles. I propose a detailed dissection of the exclusion mechanism. - Characterisation of the histone acetyltransferases and deacetylases. I propose detailed characterisation of the essential nuclear enzymes, factors they associate with, histone residues they modify and impact on gene regulation. - Hundreds of post-transcriptional regulatory 3’-untranslated regions have been identified using a high-throughput genetic screen. I propose identification of regulatory RNA-binding proteins, the genes they regulate and the underpinning regulatory mechanisms. The proposed studies will fill major gaps in understanding, illuminating mechanisms of VSG allelic exclusion, chromatin-based control and post-transcriptional regulons. How eukaryotic cells express only one gene from the largest gene families, in particular, remains a major unresolved question. Potentially druggable targets that emerge will also present opportunities for further collaboration with colleagues in the Wellcome Trust Centre for Anti-Infectives Research.