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Title: Epigenetic control of transcription in the African trypanosome, Trypanosoma brucei
Author: Kerry, Louise Elizabeth
ISNI:       0000 0004 7657 9178
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Trypanosoma brucei relies on an essential Variant Surface Glycoprotein (VSG) coat for survival in the mammalian bloodstream. A single VSG gene is transcribed by RNA polymerase I (Pol I) in a strictly monoallelic fashion from one of multiple telomeric VSG expression sites (ES). The epigenetic mechanisms that maintain monoallelic expression of a single VSG remain unclear. The goal of this research was to advance our understanding of the epigenetic factors that contribute to regulation of Pol I transcription in T. brucei and to evaluate epigenetic drug targets as novel anti-parasitic agents. The distribution of the histone H3K4me3 modification at Pol I transcribed loci was determined by ChIP-qPCR. The H3K4me3 modification was not enriched within the VSG ESs or the Pol I rDNA transcription unit, suggesting that this modification does not correlate with active Pol I promoters, as is the case in higher eukaryotes. ChIP-qPCR was also used to ascertain the epigenetic state of the pre-active ESs present in T. brucei DDR cells that express two VSGs from two active ESs. Characterisation of the DDR parasites showed that both ESs appear to be in a pre-active state, and that the singularity of expression site body contributes to monoallelic expression of the VSG genes. As VSG ESs are appealing targets for anti-trypanosomal chemotherapies, I evaluated the potential of histone methyltransferase inhibitors (HKMTI) and Pol I inhibitors as novel trypanocidal agents. The HKMTI and Pol I inhibitors cause parasite cell death in a time- and dose-dependant manner with favourable selectivity compared with mammalian cells. The Pol I inhibitors are toxic to trypanosomes as a result of specifically blocking T. brucei Pol I transcription. Whereas, cell death in the HKMTI treated parasites appears to be due to off-target effects. Ultimately, this research could contribute to the development of novel treatments for Human African Trypanosomiasis.
Supervisor: Rudenko, Gloria ; Fuchter, Matthew Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral