Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear locations.

Much of the success of Plasmodium falciparum in establishing persistent infections is attributed to immune evasion through antigenic variation. This process involves periodically exchanging variants of the major surface antigen PfEMP1, a protein also responsible for parasite cytoadherence. PfEMP1 is encoded by genes of the 60-member var family, located at subtelomeric and internal chromosome loci. The active or silenced state of var genes is heritable, and its control by nonsequence information remains puzzling. Using FISH analysis, we demonstrate that both internal and subtelomeric var genes are positioned at the nuclear periphery in their repressed state. Upon activation, the same var genes are still found in the periphery, indicating that this zone can be transcriptionally competent, rather than uniformly silenced. However, activation of a var gene is linked with altered positioning at the nuclear periphery, with subtelomeric var loci exiting chromosome end clusters and being relocated to distinct nuclear sites. Serial sectioning of parasite nuclei reveals areas of both condensed and noncondensed chromatin at the nuclear periphery. Our results demonstrate that regulation of antigenic variation is associated with subnuclear position effects and point to the existence of transcriptionally permissive perinuclear zones for var genes.