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Instituto de Parasitología y Biomedicina
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ANTIGENIC VARIATION IN TRYPANOSOMA BRUCEI; NUCLEAR ARCHITECTURE, FACTORS AND REGULATION
Group Leader
    Miguel Angel Navarro Carretero     
Staff Research Predoctoral
  • Carlos Cordón Obras     
  • Domingo Isaac Rojas Barros     
  • Manuel Alejandro Saldivia Concepción     
  • Andreu Saura Rebollar     
Technical Assistants
  • Isabel Beatriz Vidal Cobo     
Authorized Staff
  • Jean Mathieu Bart      
  • Pablo Tristán Ramos     

By changes in the variant surface glycoprotein (VSG) coat, the bloodstream form of the parasite undergoes antigenic variation and eludes the host immune response. However, at a given time, only one VSG type is expressed on the surface of the cell. This is achieved by the transcription of only one telomeric expression site (ES) locus, out of twenty different ESs. Once active, high transcription of an ES is maintained during many generations. Previous work has shown that ES transcriptional activation can occur epigenetically, representing a genuine example of mono-allelic expression of a multigene family. We have recently obtained evidence that the recruitment of a single ES by a discrete transcriptional nuclear site, the ES Body, defines the mechanism responsible for VSG mono-allelic expresión (Navarro and Gull 2001). The main focus of our research is to investigate the unique transcriptional body we have recently identified in the nucleus of the protozoan parasite Trypanosoma brucei.

 

Nuclear architecture underlying developmentally regulated pol I transcription in Trypanosoma brucei

 

African trypanosomes are characterized by one of the more complex genetic mechanisms of immune-response evasion developed by a pathogen and serve as a model system for other parasites that undergo antigenic variation. Increasing interest in the significance of nuclear architecture in the regulation of gene expression makes Trypanosoma brucei an exceptional model system, since the two main surface-protein genes (VSGs and procyclin) are transcribed by the highly compartmentalized RNA polymerase I. In our lab we focus in understanding the influence of chromosomal nuclear spatial constraints in T. brucei transcriptional regulation.

 

Nuclear repositioning of chromosomes plays a significant role in accomplishing proper gene expression control. Accurate timing in the positioning of chromosome sites and association with particular nuclear structures are necessary to coordinate gene regulation. In the insect procyclic stage, non-excluding transcription of procyclin alleles appears to not be required for association with a single extranucleolar body, in contrast to the active VSG ES in the bloodstream form associated to the ES Body. Upon differentiation from the bloodstream to the insect procyclic stage the active VSG-ES promoter, previously, exclusively localized in the ESB, undergoes a rapid repositioning to the nuclear periphery with concomitant loss of the ESB. After repositioning, the active ES promoter undergoes chromatin condensation, as revealed by reduced accessibility of the GFP-lacI to Lac operator sequences inserted in the chromosome (Landeira and Navarro, 2007).

 

Our findings in trypanosome nuclear chromosome dynamics suggest that these phenomena are extremely conserved, since T. brucei is in a distal position in the eukaryotic cell linage. Nuclear envelope repositioning of chromosome loci in T. brucei influences pol I transcription suggesting nuclear architecture plays a global role in regulation of transcription in eukaryotes.

 

FUNDING AGENCIES

 

- RED RETICS. RED FIS, , RD12/0018/0015, (2013 - 2013).

- Identification of trypanocidal kinase inhibitors. PROYECTO, Convocatoria Tres Cantos Open Lab Foundation, PROJECT-TC007, (2011 - 2013).

- La quinasa TOR como diana terapéutica frente a enfermedades tropicales protozoarias.. PROYECTO, PROYEX-10, CTS-5841, (2011 - 2014).

- Análisis molecular y funcional de nuevos complejos TOR (Target Of Rapamycin) y nuevas rutas de señalización en tripanosomas africanos. PROYECTO, INV.FUND.NO ORIENTADA.- BIOMEDICINA, SAF2009-07587, (2010 - 2012).

- Red RICET. RED FIS, FONDO DE INVESTIGACION SANITARIA, RD06/0021/0010, (2007 - 2012).

- Caracterización funcional de TOR como diana terapéutica potencial en Trypanosoma brucei. PROYECTO, PROGRAMA NACIONAL DE BIOMEDICINA, SAF2006-01763, (2006 - 2009).

 

 

SELECTED PUBLICATIONS

 

A. Barquilla, M. Saldivia, R. Diaz R, J.M. Bart, I. Vidal, E. Calvo, M. Hall, M. Navarro.
"Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei".
Proceeding of National Academy of Sciences, U S A. 2012. Epub 2012/08/22.
doi: 10.1073/pnas.1210465109. PubMed PMID: 22908264.
Faculty of 1000 Biology: PDF

 

K. N. Dubois, S. Alsford, j.m. Holden, J.M., Buisson, M. Swiderski, J. M. Bart, P. Bastin, J. D. Barry, M. Navarro, D. Horn, J. D. Aitchison, M. Rout, M. C. Field, M. C.
"NUP-1 Is a Large Coiled-Coil Nucleoskeletal Protein in Trypanosomes with Lamin-Like Functions".
PLoS Biology.2012. 10, e1001287.PDF

 

Diaz-Gonzalez, R., Kuhlmann, F.M., Galan-Rodriguez, C., Madeira da Silva, L., Saldivia, M., Karver, C.E., Rodriguez, A., Beverley, S.M., Navarro, M., and Pollastri, M.P.
"The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing".
PLoS Neglected  Tropical Diseases. 5, e1297. 2011.PDF

 

T. C. Leandro de Jesus, R. Rosito Tonelli, S. C. Nardelli, L. Silva Augusto, M. C. M. Motta, W. Girard-Dias, K. Miranda, P. Ulrich, V. Jimenez, A. Barquilla, M. Navarro, R. Docampo, and S. Schenkman
"TOR-like 1 kinase is involved in the control of polyphosphate levels and acidocalcisome maintenance in Trypanosoma brucei"
The Journal of Biological Chemistry. 2010. 285: 24131-24140. PDF

 

D. Landeira, J.Mat Bart, D. Van Tyne and M. Navarro
      "Cohesin regulates VSG monoallelic expression in Trypanosoma brucei"
The Journal of Cell Biology, 2009. 186 (2): 243-254. PDF

Faculty of 1000 Biology: http://www.f1000biology.com/article/id/1164554/evaluation

 

A. Barquilla, and M. Navarro
"Trypanosome TOR Complex 2 Functions in Cytokinesis".
Cell Cycle, 2009. 8(5): 697-9. PDF

 

X. Peñate, D. López-Farfán, D. Landeira, A. Wentland, I. Vidal and M. Navarro
"RNA polymerase II subunit RPB7 is required for RNA polymerase I mediated transcription in Trypanosoma brucei"
EMBO Reports 2009. 10 (2): 252-7. PDF
Faculty of 1000 Biology: http://www.f1000biology.com/article/id/1157414/evaluation

 

A. Barquilla and M. Navarro. "Trypanosome TOR as a Major Regulator of Cell Growth and Autophagy "
Autophagy 2009. 5(2): 256-8. PDF

 

A. Barquilla, J.L. Crespo M. Navarro
"Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation"
Proceeding of National Academy of Sciences, U S A 2008. 23 105(38):14579-84. PDF
 Faculty of 1000 Biology: http://www.f1000biology.com/article/id/1123193/evaluation

 

D. Landeira and M. Navarro
"Nuclear repositioning of the VSG promoter during developmental silencing in Trypanosoma brucei"
The Journal of Cell Biology, 2007. 176 (2): 133-139. PDF
Faculty of 1000 Biology: http://www.f1000biology.com/article/id/1066070/evaluation

 

M. Navarro and K. Gull
"A pol I transcriptional body associated with the VSG mono-allelic expression in Trypanosoma brucei". PDF
Nature. 2001, 414:759-763
Cover: "The masked trypanosome"

 

Reviews

 

Navarro, M., Penate, X., Landeira, D., and Lopez-Farfan, D.
"Role of RPB7 in RNA pol I transcription in Trypanosoma brucei".
Molecular and Biochemical Parasitology, 2011. 180, 43-44. PDF

 

M. Navarro, X. Penate and D. Landeira
"Nuclear architecture underlying gene expression in Trypanosoma brucei"
Trends in Microbiology, 2007. 5(6): 163-270. PDF

 

 

Ph. D. THESES

 

Tesis de Doctorado:

"Análisis funcional de la RNA polimerasa I de Trypanosoma brucei"

Estudiante: Xenia Peñate Peñate

Instituto de Parasitología y Biomedicina "López-Neyra"

Sobresaliente "Cum Laude".

23/11/2007

 

Tesis de Doctorado:

"Dinámica y compartimentación subnuclear de genes regulados en el desarrollo en Trypanosoma brucei"

Estudiante: David Landeira Frías

Instituto de Parasitología y Biomedicina "López-Neyra"

Sobresaliente "Cum Laude".

11/02/2008

 

Tesis de Doctorado:
"Caracterización funcional de la proteína quinasa TOR (TargetofRapamycin) en T. brucei".
Estudiante: Antonio A. Barquilla Panadero
Instituto de Parasitología y Biomedicina "López-Neyra"
Universidad de Granada
Calificación: Sobresaliente "Cum laude"

01/2004- 13-7-2009

 

Tesis de Doctorado:
"Función de la RPB7, la SUMO E3 ligasaTbSIZ1 y la SUMOilación de la cromatina en la regulación del sitio de expresión de la VSG en Trypanosoma brucei."
Estudiante: Diana Carolina López-Farfán
Instituto de Parasitología y Biomedicina "López-Neyra"
Universidad de Granada
Calificación: Sobresaliente "Cum laude"

01/2006 – 09/2011

 

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