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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: eLife, 20 May 2014, Vol.3, pp.e02324
    Description: We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.DOI: http://dx.doi.org/10.7554/eLife.02324.001.
    Keywords: Trypanosoma Brucei ; Antigenic Variation ; Developmental Reprogramming ; Expression Site Attenuation ; Monoallelic Expression ; Variant Surface Glycoprotein (Vsg) ; Antigenic Variation ; Gene Expression Regulation, Developmental ; Genes, Protozoan ; Protozoan Proteins -- Genetics ; RNA, Protozoan -- Isolation & Purification ; Trypanosoma Brucei Brucei -- Genetics
    E-ISSN: 2050-084X
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  • 3
    Language: English
    In: PLoS Pathogens, 01 April 2017, Vol.13(4), p.e1006324
    Description: For persistent infections of the mammalian host, African trypanosomes limit their population size by quorum sensing of the parasite-excreted stumpy induction factor (SIF), which induces development to the tsetse-infective stumpy stage. We found that besides this cell density-dependent mechanism, there exists a second path to the stumpy stage that is linked to antigenic variation, the main instrument of parasite virulence. The expression of a second variant surface glycoprotein (VSG) leads to transcriptional attenuation of the VSG expression site (ES) and immediate development to tsetse fly infective stumpy parasites. This path is independent of SIF and solely controlled by the transcriptional status of the ES. In pleomorphic trypanosomes varying degrees of ES-attenuation result in phenotypic plasticity. While full ES-attenuation causes irreversible stumpy development, milder attenuation may open a time window for rescuing an unsuccessful antigenic switch, a scenario that so far has not been considered as important for parasite survival.
    Keywords: Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 4
    Language: English
    In: PLoS Pathogens, 01 February 2016, Vol.12(2), p.e1005439
    Description: Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.
    Keywords: Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 5
    In: Molecular Microbiology, February 2008, Vol.67(4), pp.762-771
    Description: Post‐translational histone modifications have been studied intensively in several eukaryotes. It has been proposed that these modifications constitute a ‘histone code’ that specifies epigenetic information for transcription regulation. With a limited number of histone‐modifying enzymes, implying less redundancy, represents an excellent system in which to investigate the function of individual histone modifications and histone‐modifying enzymes. In this study, we characterized the acetylation of lysine 4 of histone H4 (H4K4), the most abundant acetylation site in histones. Because of the large sequence divergence of histones, we generated highly specific antibodies to acetylated and unmodified H4K4. Immunofluorescence microscopy and Western blots with sorted cells revealed a strong enrichment of unmodified H4K4 in S phase and suggested a G1/G0‐specific masking of the site, owing to non‐covalently binding factors. Finally, we showed that histone acetyltransferase 3 (HAT3) is responsible for H4K4 acetylation and that treatment of cells with the protein synthesis inhibitor cycloheximide led to an almost instantaneous loss of unmodified H4K4 sites. As HAT3 is located inside the nucleus, our findings suggest that newly synthesized histone H4 with an unmodified K4 is imported rapidly into the nucleus, where it is acetylated, possibly irreversibly.
    Keywords: Acetates ; Protein Synthesis ; Histones;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 6
    Language: English
    In: PLoS Biology, 2008, Vol.6(7), p.e161
    Description: To evade the host immune system, several pathogens periodically change their cell-surface epitopes. In the African trypanosomes, antigenic variation is achieved by tightly regulating the expression of a multigene family encoding a large repertoire of variant surface glycoproteins (VSGs). Immune evasion relies on two important features: exposing a single type of VSG at the cell surface and periodically and very rapidly switching the expressed VSG. Transcriptional switching between resident telomeric VSG genes does not involve DNA rearrangements, and regulation is probably epigenetic. The histone methyltransferase DOT1B is a nonessential protein that trimethylates lysine 76 of histone H3 in Trypanosoma brucei . Here we report that transcriptionally silent telomeric VSG s become partially derepressed when DOT1B is deleted, whereas nontelomeric loci are unaffected. DOT1B also is involved in the kinetics of VSG switching: in ΔDOT1B cells, the transcriptional switch is so slow that cells expressing two VSGs persist for several weeks, indicating that monoallelic transcription is compromised. We conclude that DOT1B is required to maintain strict VSG silencing and to ensure rapid transcriptional VSG switching, demonstrating that epigenetics plays an important role in regulating antigenic variation in T. brucei . ; The surface of , a unicellular parasite that lives in the bloodstream of its mammalian host, is coated with glycoprotein (VSG) molecules. To evade elimination by the immune system, this parasite replaces its coat with one tailored from another glycoprotein variant. Even though there are hundreds of genes in the genome, this process, called antigenic variation, works because all are silenced except for the one that encodes the current coat. In this work, we show that the chromatin-modifying enzyme DOT1B helps to epigenetically regulate the number of VSGs each parasite can have at a time at the surface and how fast each parasite can switch from one coat to another. In parasites lacking DOT1B, silent genes become partially active and the switch from one VSG to another slows down, allowing two different VSGs to appear on the surface of an individual parasite at the same time. Our studies reveal the importance of epigenetics in regulating genes and provide new insights toward the understanding of this unique survival device. ; Antigenic variation in relies on monoallelic expression of a multigene family. New evidence shows that a chromatin-modifying enzyme prevents simultaneous expression of different proteins at the parasite's surface.
    Keywords: Research Article ; Cell Biology ; Genetics And Genomics ; Infectious Diseases ; Microbiology ; Molecular Biology
    ISSN: 1544-9173
    E-ISSN: 1545-7885
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