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Regulation of variant antigen gene expression in African trypanosomes


   Department of Life Sciences

   Applications accepted all year round  Competition Funded PhD Project (Students Worldwide)

About the Project

We investigate the molecular biology of African trypanosomes, with a particular focus on the epigenetic control of gene expression. Trypanosomes are single-celled eukaryotes which are easily manipulated in vitro. They provide an experimentally amenable system for studying gene expression in a disease-causing organism. Trypanosomes are protected by a dense Variant Surface Glycoprotein (VSG) coat, which is expressed from a gene located in one of multiple telomeric VSG expression site transcription units. Expression sites are transcribed at an extremely high rate, allowing the trypanosome to express large amounts of coat protein from a single-copy gene.

We would like to understand how the VSG expression sites are turned on and off, and the mechanism behind the stringent restriction that ensures that only one expression site is kept active at a time (Budzak et al PNAS 2019 116:33 16561-16570). In addition, we would like to understand how silent areas of the trypanosome genome are kept inactive, and how transcriptional control, including the epigenetic control of VSG expression is mediated. We would like to investigate the role of epigenetic gene control mechanisms including chromosome interactions, epigenetic modifications and nuclear positioning.  In addition we would like to investigate the role of RNA processing in VSG expression site control, and the role of novel nuclear bodies facilitating this.

These questions will be investigated using molecular approaches including genetic modification of trypanosomes (gene knock-outs and modification using CRISPR-Cas9), RNA interference (RNAi), ChIP, chromosome conformation capture, and super-resolution microscopy techniques.  


References

1. Budzak, J., Jones, R., Tschudi, C., Kolev, N.G. and Rudenko G. (2022) An assembly of nuclear bodies associates with the active VSG expression site in African trypanosomes. Nature Communications 13(1):101. PMID: 35013170.
2. Davies, C., Ooi, C.-P., Sioutas, G., Hall, B.S., Sidhu, H., Butter, F., Alsford, S., Wickstead, B. and Rudenko G. (2021) TbSAP is a novel chromatin protein repressing metacyclic Variant Surface Glycoprotein expression sites in bloodstream form Trypanosoma brucei. Nucleic Acids Research 49(6): 3242-3262. PMID: 33660774.
3. Budzak, J., Kerry, L.E., Aristodemou, A., Hall, B.S., Witmer, K., Kushwaha, M., Davies, C., Povelones, M.L., McDonald, J.R., Sur, A., Myler, P.J. and Rudenko G. (2019) Dynamic colocalization of 2 simultaneously active VSG expression sites within a single expression-site body in Trypanosoma brucei. Proceedings National Academy of Sciences 116(33), 16561-16570. PMID: 31358644.
4. Ooi, C.P., Smith, T.K., Gluenz, E., Wand, N.V., Vaughan, S. and Rudenko G. (2018) Blocking Variant Surface Glycoprotein synthesis alters endoplasmic reticulum exit sites/ Golgi homeostasis in Trypanosoma brucei. Traffic 19: 391-405. PMID: 29533496.
5. Ooi, C.P. and Rudenko G. (2017) How to create coats for all seasons: elucidating antigenic variation in African trypanosomes. Emerging Topics in Life Sciences 1: 593-600.
6. Ridewood, S., Ooi, C.P., Hall, B., Trenaman, A., Wand, N.V., Scherwitzl, I., Narayanan, M.S. and Rudenko G. (2017) The role of genomic location and flanking 3’UTR in the generation of functional levels of Variant Surface Glycoprotein in Trypanosoma brucei. Molecular Microbiology 106(4), 614-634. PMID: 28906055
7. Kerry, L.E., Pegg, E.E., Cameron, D.P., Budzak, J., Poortinga, G., Hannan, K., Hannan, R.D. and Rudenko G. (2017) Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis. PLoS Neglected Tropical Diseases 11(3): e0005432. PMID: 28263991.
8. Cheung, J.L.Y., Wand, N.V., Ooi, C.P., Wheeler, R. and Rudenko G. (2016). Blocking synthesis of the Variant Surface Glycoprotein coat in Trypanosoma brucei leads to an increase in macrophage phagocytosis due to reduced clearance of surface coat antibodies. PLoS Pathogens 12(11):e1006023. PMID: 27893860.
9. Stanne, T., Narayanan, M.S., Ridewood, S., Ling, A., Witmer, K., Kushwaha, M., Wiesler, S., Wickstead, B., Wood, J. and Rudenko G. (2015) Identification of the ISWI chromatin remodeling complex of the early branching eukaryote Trypanosoma brucei. Journal of Biological Chemistry 290(45): 26954-26967. PMID: 26657756
10. Rudenko G. (2011) African trypanosomes: the genome and adaptations for immune evasion. Essays in Biochemistry 51: 47-62. PMID: 22023441

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