1. The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Australia
2. Department of Microbiology, Monash University, Clayton 3800, Australia
3. Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Parkville 3050, Australia
4. Papua New Guinea Institute of Medical Research, Goroka EHP 441, Papua New Guinea

Correspondence to: Alan F. Cowman¹ Correspondence and requests for materials should be addressed to A.F.C. (Email: cowman@wehi.edu.au).

Abstract

Mono-allelic expression of gene families is used by many organisms to mediate phenotypic variation of surface proteins. In the apicomplexan parasite Plasmodium falciparum, responsible for the severe form of malaria in humans, this is exemplified by antigenic variation of the highly polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1)^{1, 2}. PfEMP1, encoded by the 60-member vargene family^{3, 4, 5, 6}, represents a major virulence factor due to its central role in immune evasion and intravascular parasite sequestration. Mutually exclusive expression of PfEMP1 is controlled by epigenetic mechanisms involving chromatin modification and perinuclear var locus repositioning^{7, 8}. Here we show that a var promoter mediates the nucleation and spreading of stably inherited silenced chromatin. Transcriptional activation of this promoter occurs at the nuclear periphery in association with chromosome-end clusters. Additionally, the var promoter sequence is sufficient to infiltrate a transgene into the allelic exclusion programme of var gene expression, as transcriptional activation of this transgene results in silencing of endogenous var gene transcription. These results show that a var promoter is sufficient for epigenetic silencing and mono-allelic transcription of this virulence gene family, and are fundamental for our understanding of antigenic variation in P. falciparum. Furthermore, the PfEMP1 knockdown parasites obtained in this study will be important tools to increase our understanding of P. falciparum-mediated virulence and immune evasion.

1. The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Australia
2. Department of Microbiology, Monash University, Clayton 3800, Australia
3. Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Parkville 3050, Australia
4. Papua New Guinea Institute of Medical Research, Goroka EHP 441, Papua New Guinea

Correspondence to: Alan F. Cowman¹ Correspondence and requests for materials should be addressed to A.F.C. (Email: cowman@wehi.edu.au).

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