ThePlasmodium falciparumhistone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood stage parasites

Abstract

The malaria parasitePlasmodium falciparumemploys antigenic variation of the virulence factorP. falciparumerythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copyvargene family.vargenes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singularvargene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator ofvargene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 invargene regulation. We demonstrate that PfSET10 is not required for mutually exclusivevargene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulatingvargene expression and not required for blood stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.