5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites

Abstract

Summary In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long‐term chronic infection of the host. This is achieved by sequential expression of a single member of the 60‐member var family. Here we show that the 5′ flanking region nucleates epigenetic events strongly linked to the maintenance of mono‐allelic var gene expression pattern during parasite proliferation. Tri‐ and dimethylation of histone H3 lysine 4 peak in the 5′ upstream region of transcribed var and during the poised state (non‐transcribed phase of var genes during the 48 h asexual life cycle), ‘bookmarking’ this member for re‐activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5′ flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5′ flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.

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Cited by papers we hold 7

• PfSET2 Is Involved in Genome Organization of Var Gene Family in Plasmodium falciparum · 2023
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• PfSWIB, a potential chromatin regulator for var gene regulation and parasite development in Plasmodium falciparum · 2020
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• Silence, activate, poise and switch! Mechanisms of antigenic variation in P lasmodium falciparum · 2013
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• Polysome profiling reveals translational control of gene expression in the human malaria parasite Plasmodium falciparum · 2013
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• A Major Role for the Plasmodium falciparum ApiAP2 Protein PfSIP2 in Chromosome End Biology · 2010
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• Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors · 2009
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• Sir2 Paralogues Cooperate to Regulate Virulence Genes and Antigenic Variation in Plasmodium falciparum · 2009
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