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Differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in Plasmodium falciparum.

Rosenberg E, Ben-Shmuel A, Shalev O, Sinay R, Cowman A, Pollack Y - PLoS ONE (2009)

Bottom Line: Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue.By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications.As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of Negev, Beer-Sheva, Israel.

ABSTRACT
1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

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Analysis of expression of var and non-var exported genes upon exposure to oxidative stress in genetically modified parasites.A. The relative change in expression of the ups A, B, and C var subtypes upon exposure to 10 µM tBHP in Δpfsir2 parasites in relation to unexposed Δpfsir2 parasites. B. Analysis of expression of exported non-var genes upon exposure to oxidative stress in Δpfsir2 parasites. C. Analysis of expression of hdhfr – the gene under control of an upsC element in the 3D7/upsC transgenic line – upon exposure to 10 µM tBHP. Stress induction, cDNA production and qPCR analysis were performed as described in the legend to Fig. 1. Error bars represent mean of triplicates ± SEM.
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pone-0006991-g004: Analysis of expression of var and non-var exported genes upon exposure to oxidative stress in genetically modified parasites.A. The relative change in expression of the ups A, B, and C var subtypes upon exposure to 10 µM tBHP in Δpfsir2 parasites in relation to unexposed Δpfsir2 parasites. B. Analysis of expression of exported non-var genes upon exposure to oxidative stress in Δpfsir2 parasites. C. Analysis of expression of hdhfr – the gene under control of an upsC element in the 3D7/upsC transgenic line – upon exposure to 10 µM tBHP. Stress induction, cDNA production and qPCR analysis were performed as described in the legend to Fig. 1. Error bars represent mean of triplicates ± SEM.

Mentions: We further pondered whether this differential effect on var genes is due to the difference in the upstream sequence of the subtypes' promoters or whether it is due to their position along the chromosome. To address this question, we used the two genetically modified parasite lines described in Materials and Methods. We hypothesized that pfsir2 may act as a leading candidate for involvement in the stress response of var genes. In light of this possibility, when repeating the exposure to stress on a pfsir2 knockout line, a different pattern was observed – stress up-regulated all three subtypes (Fig. 4A). No significant change was observed when examining the other exported genes (Fig. 4B) leading to the conclusion that the upsA and upsB down-regulation upon stress exposure is a pfsir2, hence a positional, dependent process.


Differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in Plasmodium falciparum.

Rosenberg E, Ben-Shmuel A, Shalev O, Sinay R, Cowman A, Pollack Y - PLoS ONE (2009)

Analysis of expression of var and non-var exported genes upon exposure to oxidative stress in genetically modified parasites.A. The relative change in expression of the ups A, B, and C var subtypes upon exposure to 10 µM tBHP in Δpfsir2 parasites in relation to unexposed Δpfsir2 parasites. B. Analysis of expression of exported non-var genes upon exposure to oxidative stress in Δpfsir2 parasites. C. Analysis of expression of hdhfr – the gene under control of an upsC element in the 3D7/upsC transgenic line – upon exposure to 10 µM tBHP. Stress induction, cDNA production and qPCR analysis were performed as described in the legend to Fig. 1. Error bars represent mean of triplicates ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2734987&req=5

pone-0006991-g004: Analysis of expression of var and non-var exported genes upon exposure to oxidative stress in genetically modified parasites.A. The relative change in expression of the ups A, B, and C var subtypes upon exposure to 10 µM tBHP in Δpfsir2 parasites in relation to unexposed Δpfsir2 parasites. B. Analysis of expression of exported non-var genes upon exposure to oxidative stress in Δpfsir2 parasites. C. Analysis of expression of hdhfr – the gene under control of an upsC element in the 3D7/upsC transgenic line – upon exposure to 10 µM tBHP. Stress induction, cDNA production and qPCR analysis were performed as described in the legend to Fig. 1. Error bars represent mean of triplicates ± SEM.
Mentions: We further pondered whether this differential effect on var genes is due to the difference in the upstream sequence of the subtypes' promoters or whether it is due to their position along the chromosome. To address this question, we used the two genetically modified parasite lines described in Materials and Methods. We hypothesized that pfsir2 may act as a leading candidate for involvement in the stress response of var genes. In light of this possibility, when repeating the exposure to stress on a pfsir2 knockout line, a different pattern was observed – stress up-regulated all three subtypes (Fig. 4A). No significant change was observed when examining the other exported genes (Fig. 4B) leading to the conclusion that the upsA and upsB down-regulation upon stress exposure is a pfsir2, hence a positional, dependent process.

Bottom Line: Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue.By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications.As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of Negev, Beer-Sheva, Israel.

ABSTRACT
1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

Show MeSH
Related in: MedlinePlus