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      Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors

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          Abstract

          Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that P. falciparum heterochromatin protein 1 (PfHP1) binds specifically to H3K9me3 but not to other repressive histone methyl marks. Based on nuclear fractionation and detailed immuno-localization assays, PfHP1 constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with virulence gene arrays in subtelomeric and chromosome-internal islands and a high correlation with previously mapped H3K9me3 marks. These include not only var genes, but also the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host–parasite interactions. In addition, we identified a number of PfHP1-bound genes that were not enriched in H3K9me3, many of which code for proteins expressed during invasion or at different life cycle stages. Interestingly, PfHP1 is absent from centromeric regions, implying important differences in centromere biology between P. falciparum and its human host. Over-expression of PfHP1 results in an enhancement of variegated expression and highlights the presence of well-defined heterochromatic boundaries. In summary, we identify PfHP1 as a major effector of virulence gene silencing and phenotypic variation. Our results are instrumental for our understanding of this widely used survival strategy in unicellular pathogens.

          Author Summary

          Plasmodium falciparum causes the most severe form of malaria in humans. The high virulence of this unicellular parasite is in part related to the selective expression of members of falciparum-specific gene families. These genes encode proteins that are exported into the cytoplasm and onto the surface of infected red blood cells. To avoid recognition by the host's immune system, P. falciparum employs sequential expression of antigenically different variants of these surface proteins. While the epigenetic mechanisms responsible for such clonal expression have been studied in some detail for the major virulence gene family var, the regulation and function of other exported protein families remain elusive. Here, we identify P. falciparum heterochromatin protein 1 as a major structural component of virulence gene islands throughout the parasite genome. This factor binds specifically to a reversible histone modification, which marks these virulence loci for transcriptional silencing. Our observations suggest a unifying epigenetic strategy in the regulation of host–parasite interactions and immune evasion in P. falciparum. Furthermore, these findings have important implications for the future study of hitherto uncharacterized exported proteins with roles in parasite virulence.

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          Most cited references103

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          The global distribution of clinical episodes of Plasmodium falciparum malaria.

          Interest in mapping the global distribution of malaria is motivated by a need to define populations at risk for appropriate resource allocation and to provide a robust framework for evaluating its global economic impact. Comparison of older and more recent malaria maps shows how the disease has been geographically restricted, but it remains entrenched in poor areas of the world with climates suitable for transmission. Here we provide an empirical approach to estimating the number of clinical events caused by Plasmodium falciparum worldwide, by using a combination of epidemiological, geographical and demographic data. We estimate that there were 515 (range 300-660) million episodes of clinical P. falciparum malaria in 2002. These global estimates are up to 50% higher than those reported by the World Health Organization (WHO) and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries. Without an informed understanding of the cartography of malaria risk, the global extent of clinical disease caused by P. falciparum will continue to be underestimated.
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            Discovery of gene function by expression profiling of the malaria parasite life cycle.

            The completion of the genome sequence for Plasmodium falciparum, the species responsible for most malaria human deaths, has the potential to reveal hundreds of new drug targets and proteins involved in pathogenesis. However, only approximately 35% of the genes code for proteins with an identifiable function. The absence of routine genetic tools for studying Plasmodium parasites suggests that this number is unlikely to change quickly if conventional serial methods are used to characterize encoded proteins. Here, we use a high-density oligonucleotide array to generate expression profiles of human and mosquito stages of the malaria parasite's life cycle. Genes with highly correlated levels and temporal patterns of expression were often involved in similar functions or cellular processes.
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              Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes.

              Plasmodium falciparum-infected human erythrocytes evade host immunity by expression of a cell-surface variant antigen and receptors for adherence to endothelial cells. These properties have been ascribed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), an antigenically diverse malarial protein of 200-350 kDa on the surface of parasitized erythrocytes (PEs). We describe the cloning of two related PfEMP1 genes from the Malayan Camp (MC) parasite strain. Antibodies generated against recombinant protein fragments of the genes were specific for MC strain PfEMP1 protein. These antibodies reacted only with the surface of MC strain PEs and blocked adherence of these cells to CD36 but without effect on adherence to thrombospondin. Multiple forms of the PfEMP1 gene are apparent in MC parasites. The molecular basis for antigenic variation in malaria and adherence of infected erythrocytes to host cells can now be pursued.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                September 2009
                September 2009
                4 September 2009
                : 5
                : 9
                : e1000569
                Affiliations
                [1 ]Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basle, Switzerland
                [2 ]Department of Molecular Biology, Nijmegen Center of Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands
                [3 ]Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
                [4 ]Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia
                [5 ]School of Biological Sciences, Nanyang Technological University, Singapore
                Weill Medical College of Cornell University, United States of America
                Author notes

                Conceived and designed the experiments: CF RB JV IN AMSA SAR AFC ZB HGS TSV. Performed the experiments: CF RB JV IN FE SAR ZB TSV. Analyzed the data: CF RB JV IN BTFA SAR ZB TSV. Contributed reagents/materials/analysis tools: AMSA SAR AFC ZB HGS TSV. Wrote the paper: TSV.

                Article
                09-PLPA-RA-0517R3
                10.1371/journal.ppat.1000569
                2731224
                19730695
                942fa2ea-ec75-4213-8445-915c4528b0d7
                Flueck et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 6 April 2009
                : 7 August 2009
                Page count
                Pages: 16
                Categories
                Research Article
                Cell Biology/Gene Expression
                Cell Biology/Nuclear Structure and Function
                Genetics and Genomics/Bioinformatics
                Genetics and Genomics/Chromosome Biology
                Genetics and Genomics/Epigenetics
                Genetics and Genomics/Gene Expression
                Genetics and Genomics/Nuclear Structure and Function
                Infectious Diseases/Protozoal Infections
                Molecular Biology/Centromeres
                Molecular Biology/Chromatin Structure
                Molecular Biology/Histone Modification

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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