Medicine (Northwest Academic Centre) - Research Publications
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ItemHeterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium faiciparum(CELL PRESS, 2005-04-08)The malaria parasite Plasmodium falciparum undergoes antigenic variation to evade host immune responses through switching expression of variant surface proteins encoded by the var gene family. We demonstrate that both a subtelomeric transgene and var genes are subject to reversible gene silencing. Var gene silencing involves the SIR complex as gene disruption of PfSIR2 results in activation of this gene family. We also demonstrate that perinuclear gene activation involves chromatin alterations and repositioning into a location that may be permissive for transcription. Together, this implies that locus repositioning and heterochromatic silencing play important roles in the epigenetic regulation of virulence genes in P. falciparum.
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ItemEvidence that Plasmodium falciparum chromosome end clusters are cross-linked by protein and are the sites of both virulence gene silencing and activation(WILEY, 2006-10)The malaria parasite Plasmodium falciparum undergoes antigenic variation through allelic exclusion and variant expression of surface proteins encoded by the var gene family. Regulation of var genes is under epigenetic control and involves reversible silencing and activation that requires the physical repositioning of a var locus into a transcriptionally permissive zone of the nuclear periphery. P. falciparum chromosome ends appear to aggregate into large perinuclear clusters which house both subtelomeric and chromosome central var genes. In this study we further define the composition of telomeric clusters using fluorescent in situ hybridization, and provide evidence that chromosome end clusters are formed by cross-linking protein. In addition, we demonstrate that a subtelomeric reporter gene and a var gene remain within clusters regardless of their transcriptional status. Our findings support a model whereby a highly localized structure dedicated to the activation of a single var gene can be housed within a gene dense chromosome end cluster that is otherwise transcriptionally silent.
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ItemTranscription of multiple var genes by individual, trophozoite-stage Plasmodium falciparum cells expressing a chondroitin sulphate A binding phenotype(WILEY, 2002-03)In this study, we detected multiple var gene transcripts within single, mature trophozoite-infected red blood cells (iRBCs) bound to chondroitin sulphate A (CSA). Several of the var detected had previously been demonstrated to encode Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) variants with domains that mediated iRBC adhesion to receptors other than CSA. Parasites expressing the CSA-adherent phenotype transcribed far more of one var than of all others, but this gene was different from the two other var previously purported to encode adhesion to CSA. Previous work suggesting that only single var are transcribed by mature trophozoites needs re-examination in the light of these data from single, infected cells.
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ItemBroad analysis reveals a consistent pattern of var gene transcription in Plasmodium falciparum repeatedly selected for a defined adhesion phenotype(WILEY, 2005-05)Transcription of the majority of the members of the Plasmodium falciparum var multigene family were analysed in two isolates by a quantitative approach. Both of these isolates had been repeatedly selected for adhesion to chondroitin sulphate A (CSA) and one had also been selected for adhesion to hyaluronic acid (HA). These adhesion phenotypes are expressed by many parasites isolated from placentae and are associated with malaria disease in pregnancy. Increased transcription of the var gene var2csa, or its homologue IT4 var4, was associated with the CSA and HA adhesion phenotypes in all parasites suggesting that it was the dominant, if not the only, var gene that encoded adhesion to CSA in these allogeneic isolates. Some var genes were consistently transcribed at higher levels than others regardless of expressed adhesion phenotypes suggesting a transcriptional hierarchy. Unspliced or partial transcripts were detected for most var genes tested. These atypical var gene transcripts may have implications for the regulation of var gene transcription.