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Transcription control and immune evasion in African trypanosomes

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  • Full or part time
    Prof Gloria Rudenko
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

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.


Relevant lab publications:
1. 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.
2. 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.
3. 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.
4. 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.
5. Povelones M.L., Gluenz, E., Dembek, M., Gull, K. and Rudenko G. (2012) Histone H1 plays a role in heterochromatin formation and VSG expression site silencing in Trypanosoma brucei. PLoS Pathogens 8(11): e1003010.
6. Stanne T.M., Kushwaha M., Wand M., Taylor J.E. and Rudenko G. (2011) TbISWI regulates multiple polymerase I (Pol I)-transcribed loci and is present at Pol II transcription boundaries in Trypanosoma brucei. Eukaryotic Cell 10(7): 964-976.
7. Narayanan M., Kushwaha M., Ersfeld K., Fullbrook A., Stanne T.M. and Rudenko G. (2011) NLP is a novel transcription regulator involved in VSG expression site control in Trypanosoma brucei. Nucleic Acids Research 39(6): 2018-2031.
8. Denninger, V., Fullbrook, A., Bessat, M., Ersfeld, K. and Rudenko, G. (2010) The FACT subunit TbSpt16 is involved in cell cycle specific control of VSG expression sites in Trypanosoma brucei. Molecular Microbiology 78(2): 459-474.
9. Stanne, T. and Rudenko G. (2010) Active VSG expression sites in Trypanosoma brucei are depleted of nucleosomes. Eukaryotic Cell 9 (1): 136-147.
10. Smith, T.K., Vasileva, N., Gluenz, E., Terry, S., Portman, N., Kramer, S., Carrington, M., Michaeli, S., Gull, K. and Rudenko G. (2009) Blocking Variant Surface Glycoprotein synthesis in Trypanosoma brucei triggers a general arrest in translation initiation. PLoS ONE 4(10):e7532.
11. Rudenko, G. (2010) Epigenetics and transcriptional control in African trypanosomes. Essays in Biochemistry 48(1): 201-219.

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