title: Differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in Plasmodium falciparum.
abstract: 1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.
authors.affiliation: The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of Negev, Beer-Sheva, Israel.
authors.forename: Elli
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Amir
authors.initials: A
authors.lastname: Ben-Shmuel
authors.forename: Oshrit
authors.initials: O
authors.lastname: Shalev
authors.forename: Rosa
authors.initials: R
authors.lastname: Sinay
authors.forename: Alan
authors.initials: A
authors.lastname: Cowman
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Pollack
mesh_terms: D000328:Adult; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics*; D017931:DNA Primers; D016054:DNA, Protozoan / Q000235:genetics; D004912:Erythrocytes / Q000469:parasitology; D017125:Genes, Protozoan; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D005810:Multigene Family; D018384:Oxidative Stress; D010963:Plasmodium falciparum / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics; D016053:RNA, Protozoan / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D016053:RNA, Protozoan; D012337:RNA, Ribosomal, 18S; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D006655:Histone Deacetylases