title: Insulator-like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum.
abstract: Plasmodium falciparum causes the deadliest form of human malaria. Its virulence is attributed to its ability to modify the infected RBC and to evade human immune attack through antigenic variation. Antigenic variation is achieved through tight regulation of antigenic switches between variable surface antigens named "P. falciparum erythrocyte membrane protein-1" encoded by the var multicopy gene family. Individual parasites express only a single var gene at a time, maintaining the remaining var genes in a transcriptionally silent state. Strict pairing between var gene promoters and a second promoter within an intron found in each var gene is required for silencing and counting of var genes by the mechanism that controls mutually exclusive expression. We have identified and characterized insulator-like DNA elements that are required for pairing var promoters and introns and thus are essential for regulating silencing and mutually exclusive expression. These elements, found in the regulatory regions of each var gene, are bound by distinct nuclear protein complexes. Any alteration in the specific, paired structure of these elements by either deletion or insertion of additional elements results in an unregulated var gene. We propose a model by which silencing and mutually exclusive expression of var genes is regulated by the precise arrangement of insulator-like DNA pairing elements.
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Jerusalem 91120, Israel.
authors.forename: Inbar
authors.initials: I
authors.lastname: Avraham
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schreier
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D019295:Computational Biology; D017124:Conserved Sequence / Q000235:genetics; D016054:DNA, Protozoan / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017125:Genes, Protozoan / Q000235:genetics; D006801:Humans; D038101:Insulator Elements / Q000235:genetics*; D007438:Introns / Q000235:genetics; D016778:Malaria, Falciparum / Q000469:parasitology*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics; D059372:Nucleotide Motifs / Q000235:genetics; D010271:Parasites / Q000235:genetics*; D010962:Plasmodium berghei / Q000235:genetics; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D016054:DNA, Protozoan; D009097:Multienzyme Complexes; D015800:Protozoan Proteins; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase