Active Transcription is Required for Maintenance of Epigenetic Memory in the Malaria Parasite Plasmodium falciparum

Ron Dzikowski, Kirk W. Deitsch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. The primary antigenic and virulence determinant expressed on the surface of infected red blood cells is PfEMP1 (P. falciparum erythrocyte membrane protein 1), a protein that mediates adhesion and sequestration of the parasites in deep tissue vascular beds. Different forms of PfEMP1 are encoded by different members of the multicopy var gene family. Expression of var genes is mutually exclusive, and by switching which gene is expressed, parasites alter both their antigenic and virulence phenotypes. Regulation of var gene expression involves gene activation, silencing, and cellular memory, and the details of the mechanisms that control this process are not understood. Here, we provide evidence that active transcription is required for the maintenance of the cellular memory that marks a specific var gene to be stably expressed through numerous cell cycles. Forcing transfected parasites to express increasing numbers of unregulated episomal var promoters led to a corresponding down-regulation of the active var gene in the parasite's genome, presumably by competing for the transcriptional machinery of the parasite and suggesting the existence of a limited nuclear factor that is required for var gene activation. This process allowed us to repress transcription of the active var gene without acting through the mechanism that controls mutually exclusive expression and, thus, to investigate the role of transcription itself in maintaining epigenetic memory. When the competing episomes were removed, the parasites did not return to their previous var gene expression pattern, but rather displayed random var gene activation, demonstrating that the epigenetic imprint that controls var gene expression had been completely erased and, thus, linking active transcription to the maintenance of cellular memory.

Original languageAmerican English
Pages (from-to)288-297
Number of pages10
JournalJournal of Molecular Biology
Volume382
Issue number2
DOIs
StatePublished - 3 Oct 2008

Bibliographical note

Funding Information:
This work was supported by a grant from the National Institutes of Health (AI 52390). The authors would like to thank Drs. Matthias Frank and Christian Epp for discussions regarding experimental design and for critical reading of the manuscript. We also thank Roy Faiman for his help in the statistical analysis. The Department of Microbiology and Immunology at Weill Medical College of Cornell University acknowledges the support of the William Randolph Hearst Foundation. K.W.D. is a Stavros S. Niarchos Scholar. R.D. is a Golda Meir Scholar and supported by the Marie Curie International Reintegration Grant (203675) and the German Israeli Foundation (2163-1725.11/2006).

Keywords

  • antigenic variation
  • epigenetics
  • gene expression
  • transcription
  • virulence

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