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  • Cell Cycle
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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: 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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  • 4
    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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  • 5
    Language: English
    In: Molecular & cellular proteomics : MCP, January 2013, Vol.12(1), pp.172-9
    Description: 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 host environments are not well understood. We developed stable isotope labeling by amino acids in cell culture in trypanosomes to compare the proteomes of two different life cycle stages. Quantitative comparison of 4364 protein groups identified many proteins previously not known to be stage-specifically expressed. The identification of stage-specific proteins helps to understand how parasites adapt to different hosts and provides new insights into differences in metabolism, gene regulation, and cell architecture. A DEAD-box RNA helicase, which is highly up-regulated in the bloodstream form of this parasite and which is essential for viability and proper cell cycle progression in this stage is described as an example.
    Keywords: Life Cycle Stages ; Dead-Box RNA Helicases -- Metabolism ; Protozoan Proteins -- Metabolism ; Trypanosoma Brucei Brucei -- Growth & Development
    ISSN: 15359476
    E-ISSN: 1535-9484
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  • 6
    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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  • 7
    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,...
    Keywords: Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 8
    Language: English
    In: Nucleic acids research, 01 November 2012, Vol.40(20), pp.10302-11
    Description: 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 the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes.
    Keywords: DNA Replication ; Histone-Lysine N-Methyltransferase -- Metabolism ; Histones -- Metabolism ; Trypanosoma Brucei Brucei -- Enzymology
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 9
    Language: English
    In: Nucleic acids research, March 2014, Vol.42(5), pp.2906-18
    Description: The anti-silencing function protein 1 (Asf1) is a chaperone that forms a complex with histones H3 and H4 facilitating dimer deposition and removal from chromatin. Most eukaryotes possess two different Asf1 chaperones but their specific functions are still unknown. Trypanosomes, a group of early-diverged eukaryotes, also have two, but more divergent Asf1 paralogs than Asf1 of higher eukaryotes. To unravel possible different functions, we characterized the two Asf1 proteins in Trypanosoma brucei. Asf1A is mainly localized in the cytosol but translocates to the nucleus in S phase. In contrast, Asf1B is predominantly localized in the nucleus, as described for other organisms. Cytosolic Asf1 knockdown results in accumulation of cells in early S phase of the cell cycle, whereas nuclear Asf1 knockdown arrests cells in S/G2 phase. Overexpression of cytosolic Asf1 increases the levels of histone H3 and H4 acetylation. In contrast to cytosolic Asf1, overexpression of nuclear Asf1 causes less pronounced growth defects in parasites exposed to genotoxic agents, prompting a function in chromatin remodeling in response to DNA damage. Only the cytosolic Asf1 interacts with recombinant H3/H4 dimers in vitro. These findings denote the early appearance in evolution of distinguishable functions for the two Asf1 chaperons in trypanosomes.
    Keywords: Histone Chaperones -- Metabolism ; Protozoan Proteins -- Metabolism ; Trypanosoma Brucei Brucei -- Metabolism
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 10
    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...
    Keywords: Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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