Epigenetics and Development



Trypanosomes developed a complicated life cycle in order to shuttle between a vertebrate host and an insect vector needed for transmission. They have to change their morphology, metabolism and energy sources to adapt to different hosts and changes in chromatin structure and nuclear architecture have been observed during this process. We use this parasite as a model organism to unravel the mechanisms that allow trypanosomes to adapt to extremely different environments in different host organisms.
In another project, we want to understand how post-translational histone modifications (PTMs) regulate cell cycle progression in Trypanosoma brucei. Individual projects are described below.



Epigenetics and developmental differentiation


Several nuclear proteins that are essential for differentiation are in the focus of research in our laboratory. For example, we discovered that the histone methyltransferase DOT1B is essential for early steps of this process … MORE


Adaptation of pathogens to different hosts


Trypanosoma brucei developed a sophisticated life cycle to adapt to different host environments. Although developmental differentiation of T. brucei has been the topic of intensive research for decades, the mechanisms responsible for adaptation to different hosts are not well understood. We developed stable isotope labeling by amino acids in cell culture (SILAC) in trypanosomes to compare the proteomes of two different life cycle stages to gain insights into the parasite's adaptation machinery. … MORE


Epigenetics and cell cycle regulation


Cell cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell cycle regulators are evolutionarily conserved in Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. For example, manipulation of histone methylation levels by over-expressing or depleting the histone methyltransferase DOT1A causes severe cell cycle-related phenotypes … MORE







Publications




Z. Cicova, M. Dejung, T. Skalicky, N. Eisenhuth, S. Hanselmann, B. Morriswood, L.M. Figueiredo, F. Butter, C.J. Janzen (2016) Two flagellar BAR domain proteins in Trypanosoma brucei with stage-specific regulation. Sci Rep. Oct 25;6:35826. doi: 10.1038/srep35826.

T.C. de Jesus, V.S. Nunes, C. Lopes Mde, D.E. Martil, L.K. Iwai, N.S. Moretti, F.C. Machado, M.L. de Lima-Stein, O.H. Thiemann, M.C. Elias, C. Janzen, S. Schenkman, J.P. da Cunha. (2016) Chromatin Proteomics Reveals Variable Histone Modifications during the Life Cycle of Trypanosoma cruzi. J Proteome Res. Jun 3;15(6):2039-51

M. Dejung, I. Subota, F. Bucerius, G. Dindar, A. Freiwald, M. Engstler, M. Boshart, F. Butter, C.J. Janzen (2016) Quantitative Proteomics Uncovers Novel Factors Involved in Developmental Differentiation of Trypanosoma brucei. PLoS Pathog. Feb 24;12(2):e1005439

R. ElBashir, J.T. Vanselow, A. Kraus, C.J. Janzen, T.N. Siegel, A. Schlosser. (2015) Fragment ion patchwork quantification for measuring site-specific acetylation degrees. Anal Chem. Oct 6;87(19):9939-45.

G. Dindar, A.M. Anger, C. Mehlhorn, S.B. Hake and C.J. Janzen (2014) Structure-guided mutational analysis reveals the functional requirements for product specificity of DOT1 enzymes. Nat Commun. Nov 12;5:5313

C. Batram, N.G. Jones, C.J. Janzen, S.M. Markert and M. Engstler (2014) Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei. elife. May 20;3:e02324

B. Pascoalino, G. Dindar, J.P. Vieira-da-Rocha, C.R. Machado, C.J. Janzen and S. Schenkman (2014) Characterization of two different Asf1 histone chaperones with distinct cellular localizations and functions in Trypanosoma brucei. Nucleic Acids Res. Mar 1;42(5):2906-18

F. Butter, F. Bucerius, M. Michel, Z. Cicova, M. Mann, C.J. Janzen (2013) Comparative proteomics of two life cycle stages of stable isotope-labeled Trypanosoma brucei reveals novel components of the parasite's host adaptation machinery. Mol Cell Proteomics. Jan;12(1):172-9.

A. Gassen, D. Brechtefeld, N. Schandry, J.M. Arteaga-Salas, L. Israel, A. Imhof, C.J. Janzen (2012) DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei. Nucleic Acids Res. Nov 1;40(20):10302-11

D. Kaufmann, A. Gassen, A. Maiser, H. Leonhardt, C.J. Janzen (2012) Regulation and spatial organization of PCNA in Trypanosoma brucei. Biochem. Biophys. Res. Commun. Mar 23;419(4):698-702

F. Bucerius, M. Kador, M. Boshart, and C.J. Janzen (2011) Reliable quantification of cell cycle-dependent mRNA abundance using fluorescence-activated cell sorting in Trypanosoma brucei. Mol. Biochem. Parasitol. Feb;175(2):205-208

F. Frederiks, T. van Welsem, G. Oudgenoeg, A.J.R. Heck, *C.J. Janzen, and *F. van Leeuwen (2010) Heterologous expression reveals distinct enzymatic activities of two DOT1 histone methyltransferases of Trypanosoma brucei. J. Cell Sci. Dec 1;123(Pt 23):4019-23.

M. Figueiredo, G.A.M. Cross, and C.J. Janzen (2009) Epigenetic regulation in African trypanosomes: a new kid on the block. Nature Rev. Microbiology, Jul; 7(7):504-513

M. Figueiredo, C.J. Janzen, and G.A.M. Cross (2008) A Histone Methyltransferase Modulates Antigenic Variation in African Trypanosomes. PLoS Biology, Jul; 1;6(7):e161

V. Mandava, C.J. Janzen, and G.A.M. Cross (2008) Trypanosome H2Bv replaces H2B in nucleosomes enriched for H3 K4 and K76 trimethylation. Biochem. Biophys. Res. Commun. Apr; 368(4):846-851

T.N. Siegel, T. Kawahara, J.A. Degrasse, C.J. Janzen, D. Horn, and G.A.M. Cross (2008) Acetylation of histone H4K4 is cell cycle regulated and mediated by HAT3 in Trypanosoma brucei. Mol. Microbiol. Feb; 67(4):762-771.

V. Mandava, J.P. Fernandez, H. Deng, C.J. Janzen, S.B. Hake, and G.A.M. Cross (2007) Histone modifications in Trypanosoma brucei. Mol. Biochem. Parasitol. Nov; 156 (1): 41-50

S. Herder, J. Voty, M. Jirku, J. Rádrová, C.J. Janzen, J. Lukes (2007) Trypanosoma brucei 29-13 strain is inducible in but not permissive for the tsetse fly vector. Exp. Parasitol. Sep; 117 (1): 111 - 114

M.A. Rubio, I. Pastar, K.W. Gaston, F.L. Ragone, C.J. Janzen, G.A.M. Cross, F. N. Papavasiliou and J. D. Alfonzo (2007) A single deaminase is required for both cytidine and adenosine editing. PNAS. May; 104 (19): 7821 - 7826

C.J. Janzen, S.B. Hake, J.E. Lowell and G.A M. Cross (2006) Selective di- or tri-methylation of histone H3 lysine 76 by two DOT1 homologues is important for cell cycle regulation in Trypanosoma brucei. May; 104 (19): 7821 - 7826 Mol. Cell. Aug; 23 (4): 497-507

C.J. Janzen, F. van Deursen, H. Shi, G.A.M. Cross, K.R. Matthews and E. Ullu (2006) Expression site silencing and life cycle progression in appear normal in Argonaute1-deficient Trypanosoma brucei. Mol. Biochem. Parasitol. Sep; 149 (1): 102-107

C.J. Janzen, J P. Fernandez, H. Deng, R. Diaz, S.B. Hake and G.A.M. Cross, (2006) Unusual histone modifications in Trypanosoma brucei. FEBS Lett. Apr 17; 580 (9): 2306-2310

J.E. Lowell, F. Kaiser, C.J. Janzen and G.A.M. Cross (2005) Histone H2AZ dimerizes with a novel variant H2B and is enriched at repetitive DNA in Trypanosoma brucei. J. Cell Sci. 15; 118: (24) 5721-5730

C.J. Janzen, F. Lander, O. Dreesen and G.A.M. Cross (2004) Telomere length regulation and transcriptional silencing in KU80 deficient Trypanosoma brucei. Nucleic Acids Res. 32: (22) 6575-84

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Collaborators




Luisa Figueiredo IMM Lisbon (PT)



Sandra Hake Adolf Butenandt Institute LMU Munich (DE)



Matthias Mann, Falk Butter MPI for Biochemistry Munich (DE)



Torsten Ochsenreiter Institute for Cell Biology Bern (CH)

Nicolai Siegel IMIB Uni Würzburg (DE)