PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum

Abstract

The variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of P. falciparum infected Red Blood Cells (iRBCs) is a critical virulence factor for malaria1. Each parasite encodes 60 antigenically distinct var genes encoding PfEMP1s, but during infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune evasion mechanism to avoid the host’s antibody responses2,3. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown4–7. Here we show that knocking out the P. falciparum variant-silencing SET gene (PfSETvs), which encodes an ortholog of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual iRBCs. PfSETvs-dependent H3K36me3 is present along the entire gene body including the transcription start site (TSS) to silence var genes. With low occupancy of PfSETvs at both the TSS of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long non-coding RNA (lncRNA). These results uncover a novel role of the PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologs of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1s may also be applied to the development of a malaria vaccine.

IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

“…4). Each parasite has the capacity to express about 60 different PfEMP1 molecules but usually only expresses one at a time (43)(44)(45). The data from experimental infections with a monoclonal parasite line indicate that among the hundreds of thousands of parasites that are released from the liver into the bloodstream, all PfEMP1 variants carried by the parasite are expressed (46,47).…”

Multifunctional Involvement of a C2H2 Zinc Finger Protein (PbZfp) in Malaria Transmission, Histone Modification, and Susceptibility to DNA Damage Response

“…The most striking phenotypic difference revealed was the loss of transmission competence of KO and Trunc parasites, thus pointing to a functional role of PbZfp during mosquito stage development. Epigenetic mechanisms have been shown to play important roles in malaria parasite development, antigenic variation, Var gene silencing, and pathogenesis (43)(44)(45)(46)(47)(48)(49)(50)(51)(52). We found that trimethylation of H3K4, H3K27, and H3K36 was completely blocked in PbZfp KO parasites.…”

Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite Plasmodium falciparum

“…Modifications to histone H3 at the lysine 9 position (H3K9) appear to play a prominent role, with acetylation of this residue (H3K9ac) associated with the single active gene and trimethylation (H3K9me3) found at the silent remaining members of the family (73,74). In addition, trimethylation of the lysine at the 36 th position of the same histone (H3K36me3) is found at all var genes and has been shown to be important for maintaining mutually exclusive expression (75,76).…”