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

PLoS Pathogens

Florian Ehlgen¹  Stuart A. Ralph¹  Igor Niederwieser²  Christian Flueck²  Till S. Voss²  Blaise T. F. Alako³  Adriana M. Salcedo-Amaya³  Richard Bartfai³  Hendrik G. Stunnenberg³  Alan F. Cowman⁴  Jennifer Volz⁴  Zbynek Bozdech⁵ 

[1] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia;Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basle, Switzerland;Department of Molecular Biology, Nijmegen Center of Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands;Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;School of Biological Sciences, Nanyang Technological University, Singapore

关键词: Plasmodium;    Genetic loci;    Gene expression;    Chromatin;    Heterochromatin;    Centromeres;    DNA transcription;    Gene regulation;   

DOI  :  10.1371/journal.ppat.1000569

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY