title: Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum.
abstract: The virulence of Plasmodium falciparum, the causative agent of the deadliest form of human malaria, is attributed to its ability to evade human immunity through antigenic variation. These parasites alternate between expression of variable antigens, encoded by members of a multicopy gene family named var. Immune evasion through antigenic variation depends on tight regulation of var gene expression, ensuring that only a single var gene is expressed at a time while the rest of the family is maintained transcriptionally silent. Understanding how a single gene is chosen for activation is critical for understanding mutually exclusive expression but remains a mystery. Here, we show that antisense long noncoding RNAs (lncRNAs) initiating from var introns are associated with the single active var gene at the time in the cell cycle when the single var upstream promoter is active. We demonstrate that these antisense transcripts are incorporated into chromatin, and that expression of these antisense lncRNAs in trans triggers activation of a silent var gene in a sequence- and dose-dependent manner. On the other hand, interference with these lncRNAs using complement peptide nucleic acid molecules down-regulated the active var gene, erased the epigenetic memory, and induced expression switching. Altogether, our data provide evidence that these antisense lncRNAs play a key role in regulating var gene activation and mutually exclusive expression.
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and.
authors.forename: Inbar
authors.initials: I
authors.lastname: Amit-Avraham
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and.
authors.forename: Guy
authors.initials: G
authors.lastname: Pozner
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and.
authors.forename: Shiri
authors.initials: S
authors.lastname: Eshar
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and.
authors.forename: Yair
authors.initials: Y
authors.lastname: Fastman
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Netanel
authors.initials: N
authors.lastname: Kolevzon
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Eylon
authors.initials: E
authors.lastname: Yavin
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; and rond@ekmd.huji.ac.il.
authors.forename: Ron
authors.initials: R
authors.lastname: Dzikowski
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020135:Peptide Nucleic Acids / Q000494:pharmacology; D010963:Plasmodium falciparum; D011401:Promoter Regions, Genetic / Q000502:physiology*; D015800:Protozoan Proteins / Q000096:biosynthesis* / Q000235:genetics; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D016053:RNA, Protozoan / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020135:Peptide Nucleic Acids; D015800:Protozoan Proteins; D062085:RNA, Long Noncoding; D016053:RNA, Protozoan; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: Plasmodium falciparum; exclusive expression; malaria; noncoding RNA; var genes