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  • 1
    Language: English
    In: Nature, November 2018, Vol.563(7729), pp.121-125
    Description: Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses-Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing-that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation.
    Keywords: Antigenic Variation -- Genetics ; Chromatin -- Genetics ; DNA, Protozoan -- Metabolism ; Genome -- Genetics ; Trypanosoma Brucei Brucei -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    Language: English
    In: Biochemical and Biophysical Research Communications, 23 March 2012, Vol.419(4), pp.698-702
    Description: ► Characterization of the proliferating cell nuclear antigen in (TbPCNA). ► TbPCNA is a suitable marker to detect replication in . ► TbPCNA distribution and regulation is different compared to closely related parasites and . As in most eukaryotic cells, replication is regulated by a conserved group of proteins in the early-diverged parasite . Only a few components of the replication machinery have been described in this parasite and regulation, sub-nuclear localization and timing of replication are not well understood. We characterized the proliferating cell nuclear antigen in (TbPCNA) to establish a spatial and temporal marker for replication. Interestingly, PCNA distribution and regulation is different compared to the closely related parasites and . TbPCNA foci are clearly detectable during S phase of the cell cycle but in contrast to they are not preferentially located at the nuclear periphery. Furthermore, PCNA seems to be degraded when cells enter G2 phase in suggesting different modes of replication regulation or functions of PCNA in these closely related eukaryotes.
    Keywords: Pcna ; Replication ; S Phase Marker ; Cell Cycle Regulation ; Trypanosoma Brucei ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 3
    Language: English
    In: Analytical Chemistry, Oct 6, 2015, Vol.87(19), p.9939(7)
    Description: The article introduces fragment ion patchwork quantification as a new mass spectrometry-based approach for the highly accurate quantification of site-specific acetylation degrees. This method merges 13C1-acetyl derivatization on the protein level, proteolysis by low-specificity proteases and quantification on the fragment ion level. Moreover, it is shown that this method enables determination of site-specific acetylation degrees of all lysine residues for all core histones of Trypanosoma brucei.
    Keywords: Acetylation – Analysis ; Mass Spectrometry – Usage ; Patchwork – Research
    ISSN: 0003-2700
    Source: Cengage Learning, Inc.
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(7), p.e0181884
    Description: Trypanosoma brucei is a protozoan flagellate that is transmitted by tsetse flies into the mammalian bloodstream. The parasite has a huge impact on human health both directly by causing African sleeping sickness and indirectly, by infecting domestic cattle. The biology of trypanosomes involves some highly unusual, nuclear-localised processes. These include polycistronic transcription without classical promoters initiated from regions defined by histone variants, trans-splicing of all transcripts to the exon of a spliced leader RNA, transcription of some very abundant proteins by RNA polymerase I and antigenic variation, a switch in expression of the cell surface protein variants that allows the parasite to resist the immune system of its mammalian host. Here, we provide the nuclear proteome of procyclic Trypanosoma brucei, the stage that resides within the tsetse fly midgut. We have performed quantitative label-free mass spectrometry to score 764 significantly nuclear enriched proteins in comparison to whole cell lysates. A comparison with proteomes of several experimentally characterised nuclear and non-nuclear structures and pathways confirmed the high quality of the dataset: the proteome contains about 80% of all nuclear proteins and less than 2% false positives. Using motif enrichment, we found the amino acid sequence KRxR present in a large number of nuclear proteins. KRxR is a sub-motif of a classical eukaryotic monopartite nuclear localisation signal and could be responsible for nuclear localization of proteins in Kinetoplastida species. As a proof of principle, we have confirmed the nuclear localisation of six proteins with previously unknown localisation by expressing eYFP fusion proteins. While proteome data of several T. brucei organelles have been published, our nuclear proteome closes an important gap in knowledge to study trypanosome biology, in particular nuclear-related processes.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Analytical chemistry, 06 October 2015, Vol.87(19), pp.9939-45
    Description: We introduce fragment ion patchwork quantification as a new mass spectrometry-based approach for the highly accurate quantification of site-specific acetylation degrees. This method combines (13)C1-acetyl derivatization on the protein level, proteolysis by low-specificity proteases and quantification on the fragment ion level. Acetylation degrees are determined from the isotope patterns of acetylated b and y ions. We show that this approach allows to determine site-specific acetylation degrees of all lysine residues for all core histones of Trypanosoma brucei. In addition, we demonstrate how this approach can be used to identify substrate sites of histone acetyltransferases.
    Keywords: Histones -- Chemistry ; Lysine -- Analysis ; Trypanosoma Brucei Brucei -- Chemistry
    ISSN: 00032700
    E-ISSN: 1520-6882
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  • 6
    Language: English
    In: Molecular and biochemical parasitology, 2011, Vol.175(2), pp.205-208
    Description: Very little is known about cell cycle-dependent regulation of mRNA in Trypanosoma brucei, the causative agent of African sleeping sickness. Methods to synchronize cell cycle progression are inefficient or subject the parasites to non-physiological conditions and stress. We developed a fluorescence-activated cell sorting-based method to analyze steady-state mRNA levels in individual cell cycle phases. Normalization of the data was the most challenging problem because internal standards for cell cycle-regulated genes are not available for trypanosomes. Hence, we introduced an external standard (so-called “spike”) to compensate for technically derived variations in processing cells and RNA samples. Validation of this method with a limited number of genes unraveled a transient up-regulation during S and G2/M phases for all mRNAs analyzed. ; Includes references ; p. 205-208.
    Keywords: Cell Cycle ; Trypanosoma Brucei ; Bsf ; Mrna Expression ; Pcf ; Quantitative Real Time Pcr ; Fluorescence-Activated Cell Sorting ; Qpcr ; Bloodstream Form ; Procyclic Form ; Facs
    ISSN: 0166-6851
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  • 7
    Language: English
    In: Biochemical and Biophysical Research Communications, 2008, Vol.368(4), pp.846-851
    Description: Some inroads have been made into characterizing histone variants and post translational modifications of histones in . Histone variant H2BV lysine 129 is homologous to H2B lysine 123, whose ubiquitination is required for methylation of H3 lysines 4 and 79. We show that H2BV K129 is not ubiquitinated, but trimethylation of H3 K4 and K76, homologs of H3 K4 and K79 in yeast, was enriched in nucleosomes containing H2BV. Mutation of H2BV K129 to alanine or arginine did not disrupt H3 K4 or K76 methylation. These data suggest that H3 K4 and K76 methylation in trypanosomes is regulated by a novel mechanism, possibly involving the replacement of H2B with H2BV in the nucleosome.
    Keywords: Chromatin Structure ; Histone Methylation ; Histone Modification ; Histone Ubiquitination ; Histone Variant ; Mass Spectrometry ; Nucleosome ; Trypanosoma Brucei ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 8
    Language: English
    In: Molecular & Biochemical Parasitology, February 2011, Vol.175(2), pp.205-208
    Description: ▶ A reliable protocol to quantify cell-cycle dependent mRNA levels. ▶ Development and validation of an external standard for normalization. ▶ Transient up-regulation of a set of mRNAs during S and G2/M phase. Very little is known about cell cycle-dependent regulation of mRNA in , the causative agent of African sleeping sickness. Methods to synchronize cell cycle progression are inefficient or subject the parasites to non-physiological conditions and stress. We developed a fluorescence-activated cell sorting-based method to analyze steady-state mRNA levels in individual cell cycle phases. Normalization of the data was the most challenging problem because internal standards for cell cycle-regulated genes are not available for trypanosomes. Hence, we introduced an external standard (so-called “spike”) to compensate for technically derived variations in processing cells and RNA samples. Validation of this method with a limited number of genes unraveled a transient up-regulation during S and G2/M phases for all mRNAs analyzed.
    Keywords: Qpcr ; Trypanosoma Brucei ; Cell Cycle ; Mrna Expression ; FACS ; Biology ; Chemistry ; Zoology
    ISSN: 0166-6851
    E-ISSN: 1872-9428
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  • 9
    Book
    Book
    Humana Press, Totowa, NJ
    Language: English
    Keywords: Life Sciences -- Protein Science
    ISBN: 978-1-62703-304-6
    Source: Springer Science & Business Media B.V.
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 May 2007, Vol.104(19), pp.7821-6
    Description: Adenosine-to-inosine editing in the anticodon of tRNAs is essential for viability. Enzymes mediating tRNA adenosine deamination in bacteria and yeast contain cytidine deaminase-conserved motifs, suggesting an evolutionary link between the two reactions. In trypanosomatids, tRNAs undergo both cytidine-to-uridine and adenosine-to-inosine editing, but the relationship between the two reactions is unclear. Here we show that down-regulation of the Trypanosoma brucei tRNA-editing enzyme by RNAi leads to a reduction in both C-to-U and A-to-I editing of tRNA in vivo. Surprisingly, in vitro, this enzyme can mediate A-to-I editing of tRNA and C-to-U deamination of ssDNA but not both in either substrate. The ability to use both DNA and RNA provides a model for a multispecificity editing enzyme. Notably, the ability of a single enzyme to perform two different deamination reactions also suggests that this enzyme still maintains specificities that would have been found in the ancestor deaminase, providing a first line of evidence for the evolution of editing deaminases.
    Keywords: RNA Editing ; Adenosine Deaminase -- Physiology ; Cytidine Deaminase -- Physiology
    ISSN: 0027-8424
    E-ISSN: 10916490
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