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      Epigenetic Regulation of Virulence Gene Expression in Parasitic Protozoa

      review-article
      1 , , 2 , ∗∗
      Cell Host & Microbe
      Cell Press

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          Abstract

          Protozoan parasites colonize numerous metazoan hosts and insect vectors through their life cycles, with the need to respond quickly and reversibly while encountering diverse and often hostile ecological niches. To succeed, parasites must also persist within individuals until transmission between hosts is achieved. Several parasitic protozoa cause a huge burden of disease in humans and livestock, and here we focus on the parasites that cause malaria and African trypanosomiasis. Efforts to understand how these pathogens adapt to survive in varied host environments, cause disease, and transmit between hosts have revealed a wealth of epigenetic phenomena. Epigenetic switching mechanisms appear to be ideally suited for the regulation of clonal antigenic variation underlying successful parasitism. We review the molecular players and complex mechanistic layers that mediate the epigenetic regulation of virulence gene expression. Understanding epigenetic processes will aid the development of antiparasitic therapeutics.

          Abstract

          Protozoan parasites colonize numerous hosts with different environments and must tightly control gene expression to ensure survival and transmission. Duraisingh and Horn review the molecular players and complex mechanistic layers mediating the epigenetic regulation of clonal antigenic variation and virulence gene expression in the parasites causing malaria and sleeping sickness.

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          Most cited references95

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          The genome of the African trypanosome Trypanosoma brucei.

          African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including approximately 900 pseudogenes and approximately 1700 T. brucei-specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.
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            Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites.

            Malaria parasites use antigenic variation to avoid immune clearance and increase the duration of infection in the human host. Variation at the surface of P. falciparum-infected erythrocytes is mediated by the differential control of a family of surface antigens encoded by var genes. Switching of var gene expression occurs in situ, mostly from telomere-associated loci, without detectable DNA alterations, suggesting that it is controlled by chromatin structure. We have identified chromatin modifications at telomeres that spread far into telomere-proximal regions, including var gene loci (>50 kb). One type of modification is mediated by a protein homologous to yeast Sir2 called PfSir2, which forms a chromosomal gradient of heterochromatin structure and histone hypoacetylation. Upon activation of a specific telomere-associated var gene, PfSir2 is removed from the promoter region and acetylation of histone occurs. Our data demonstrate that mutually exclusive transcription of var genes is linked to the dynamic remodeling of chromatin.
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              Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites.

              Clonally variant gene families underlie phenotypic plasticity in Plasmodium falciparum, a process indispensable for survival of the pathogen in its human host. Differential transcription of one of these gene families in clonal parasite lineages has been associated with chromatin modifications. Here, we determine the genome-wide distribution in P. falciparum of a histone mark of heterochromatin, trimethylation of histone H3 lysine 9 (H3K9me3), using high-resolution ChIP-chip analysis. We show that H3K9me3 is specifically associated with clonally variant gene families, which are clustered on subtelomeric and some chromosome internal regions. High levels of H3K9me3 correlate with genes localized to the nuclear periphery, implying chromosome loop formation. Disruption of the histone deacetylase PfSir2 causes changes in H3K9me3 that are discontinuous along chromosomes and associated with disrupted monoallelic transcription. Our data point to the existence of perinuclear repressive centers associated with control of expression of malaria parasite genes involved in phenotypic variation and pathogenesis.
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                Author and article information

                Contributors
                Journal
                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Cell Press
                1931-3128
                1934-6069
                11 May 2016
                11 May 2016
                : 19
                : 5
                : 629-640
                Affiliations
                [1 ]Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, 651 Huntington Avenue, Boston, MA 02115, USA
                [2 ]Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
                Author notes
                []Corresponding author mduraisi@ 123456hsph.harvard.edu
                [∗∗ ]Corresponding author dhorn@ 123456dundee.ac.uk
                Article
                S1931-3128(16)30156-1
                10.1016/j.chom.2016.04.020
                5061559
                27173931
                ae2b1b38-6abd-47d2-8e39-81cfd3017863
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
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                Review

                Microbiology & Virology
                Microbiology & Virology

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