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Transcription control and immune evasion in African trypanosomes


Department of Life Sciences

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

About the Project

Trypanosomes are unicellular eukaryotes which cause African Sleeping Sickness, which is endemic to subSaharan Africa. Trypanosomes can be easily grown as suspension cell lines in the laboratory, where they are straightforward to manipulate and genetically modify. They provide a very experimentally amenable system for investigating pathogen/ host interactions.
Bloodstream form trypanosomes are covered with a layer of Variant Surface Glycoprotein (VSG) which forms a protective coat, which can be antigenically varied during the course of an infection. An individual cell has many hundreds of VSG genes and pseudogenes, of which only one is expressed at a time from a VSG expression site transcription unit. Although trypanosomes have about 20 VSG expression sites, only one is transcribed at a time in a stringent monoallelic fashion. We would like to understand the “counting mechanism” behind this transcriptional control. Similarly, we would like to understand how silent areas of the trypanosome genome are kept inactive. We are currently investigating the role of a number of chromatin proteins for their role in VSG expression site silencing.
Second, we have shown that VSG is essential in bloodstream form trypanosomes, and that blocking its synthesis triggers a very precise cell-cycle arrest before cell division. We would like to understand how the protective VSG coat is maintained. We would also like to dissect the molecular mechanisms behind how its synthesis is sensed during the cell-cycle.

We are approaching these questions using molecular techniques including genetic modification (gene knock-outs), tetracycline inducible double-stranded RNA interference (RNAi) and flow cytometry of cells containing genes encoding fluorescent proteins inserted into different transcriptionally silent genomic locations.

Lab homepage: http://rudenkolab.co.uk/

Funding Notes

We are waiting to hear if we have been successful in receiving a Dept studentship on a collaborative PhD studentship investigating the transcriptional control of VSG expression sites.


References

Relevant lab publications:
1. 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.
2. 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.
3. 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.
4. Maree, J.P., Povelones, M.L., Clark, D.J., Rudenko, G., Patterton, H.G. (2017) Well positioned nucleosomes punctuate polycistronic Pol II transcription units and flank silent VSG gene arrays in Trypanosoma brucei. Epigenetics & Chromatin 10:14.
5. 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.
6. Cheung, J.L.Y., Wand, N.V., Ooi, C.P., Wheeler, R. and Rudenko G. (2016) Block in Variant Surface Glycoprotein synthesis increases Trypanosoma brucei susceptibility to phagocytosis by macrophages. PLoS Pathogens 12(11): e1006023.
7. 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.
8. Denninger V. and Rudenko G. (2014) FACT plays a major role in histone dynamics affecting VSG expression site control in Trypanosoma brucei. Molecular Microbiology 94(4) 945-962.
9. Narayanan M. and Rudenko G. (2013) TDP1 is an HMG chromatin protein facilitating RNA polymerase I transcription in African trypanosomes. Nucleic Acids Research 41(5): 2981-2992.

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