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Strict pairing of var promoters and introns is required for var gene silencing in the malaria parasite Plasmodium falciparum.

TitleStrict pairing of var promoters and introns is required for var gene silencing in the malaria parasite Plasmodium falciparum.
Publication TypeJournal Article
Year of Publication2006
AuthorsFrank M, Dzikowski R, Costantini D, Amulic B, Berdougo E, Deitsch K
JournalJ Biol Chem
Volume281
Issue15
Pagination9942-52
Date Published2006 Apr 14
ISSN0021-9258
KeywordsAlleles, Animals, Binding Sites, Blotting, Southern, Chromatin, Gene Expression Regulation, Gene Silencing, Genes, Reporter, Introns, Luciferases, Models, Genetic, Parasites, Phenotype, Plasmids, Plasmodium falciparum, Polymerase Chain Reaction, Promoter Regions, Genetic, Protozoan Proteins, Recombination, Genetic, Reverse Transcriptase Polymerase Chain Reaction, RNA, Transcription, Genetic, Transfection
Abstract

The human malaria parasite, Plasmodium falciparum, maintains a persistent infection altering the proteins expressed on the surface of the infected red blood cells, thus avoiding the host immune response. The primary surface antigen, a protein called PfEMP1, is encoded by a multicopy gene family called var. Each individual parasite only expresses a single var gene at a time, maintaining all other members of the family in a transcriptionally silent state. Previous work using reporter genes in transiently transfected plasmid constructs implicated a conserved intron found in all var genes in the silencing process. Here we have utilized episomal recombination within stably transformed parasites to generate different var promoter and intron arrangements and show that loss of the intron results in var promoter activation. Further, in multicopy plasmid concatamers, each intron could only silence a single promoter, suggesting a one-to-one pairing requirement for silencing. Transcriptionally active, "unpaired" promoters remained active after integration into a chromosome; however, they were not recognized by the pathway that maintains mutually exclusive var gene expression. The data indicate that intron/promoter pairing is responsible for silencing each individual var gene and that disruption of silencing of one gene does not affect the transcriptional activity of neighboring var promoters. This suggests that silencing is regulated at the level of individual genes rather than by assembly of silent chromatin throughout a chromosomal region, thus providing a possible explanation of how a var gene can be maintained in a silent state while the immediately adjacent var gene is transcriptionally active.

DOI10.1074/jbc.M513067200
Alternate JournalJ Biol Chem
PubMed ID16455655
PubMed Central IDPMC3941977
Grant ListR01 AI052390 / AI / NIAID NIH HHS / United States
AI 52390 / AI / NIAID NIH HHS / United States

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