title: Erasing the epigenetic memory and beginning to switch--the onset of antigenic switching of var genes in Plasmodium falciparum.
abstract: Antigenic variation in Plasmodium falciparum is regulated by transcriptional switches among members of the var gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no var background, similar to merozoites that egress from the liver where no var gene is expressed. Creating a null-var background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, var transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA vars, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent in vitro switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type per se but on intrinsic properties of each gene. We concluded that var switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in var transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching.
authors.affiliation: Department of Microbiology & Molecular Genetics, The Kuvin Center for the Study of Infectious and Tropical Diseases, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Fastman
authors.forename: Robert
authors.initials: R
authors.lastname: Noble
authors.forename: Mario
authors.initials: M
authors.lastname: Recker
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
mesh_terms: D000818:Animals; D000940:Antigenic Variation / Q000235:genetics* / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation
chemical_list: D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum