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Alterations in local chromatin environment are involved in silencing and activation of subtelomeric var genes in Plasmodium falciparum.

ABSTRACT: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var gene family, undergoes antigenic variation and plays an important role in chronic infection and severe malaria. Only a single var gene is transcribed per parasite, and epigenetic control mechanisms are fundamental in this strategy of mutually exclusive transcription. We show that subtelomeric upsB var gene promoters carried on episomes are silenced by default, and that promoter activation is sufficient to silence all other family members. However, they are active by default when placed downstream of a second active var promoter, underscoring the significance of local chromatin environment and nuclear compartmentalization in var promoter regulation. Native chromatin covering the SPE2-repeat array in upsB promoters is resistant to nuclease digestion, and insertion of these regulatory elements into a heterologous promoter causes local alterations in nucleosomal organization and promoter repression. Our findings suggest a common logic underlying the transcriptional control of all var genes, and have important implications for our understanding of the epigenetic processes involved in the regulation of this major virulence gene family.

SUBMITTER: Voss TS

PROVIDER: S-EPMC2169929 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Alterations in local chromatin environment are involved in silencing and activation of subtelomeric var genes in Plasmodium falciparum.

Voss Till S TS Tonkin Christopher J CJ Marty Allison J AJ Thompson Jennifer K JK Healer Julie J Crabb Brendan S BS Cowman Alan F AF

Molecular microbiology 20070828 1

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var gene family, undergoes antigenic variation and plays an important role in chronic infection and severe malaria. Only a single var gene is transcribed per parasite, and epigenetic control mechanisms are fundamental in this strategy of mutually exclusive transcription. We show that subtelomeric upsB var gene promoters carried on episomes are silenced by default, and that promoter activation is sufficient to silence a ...[more]

PMID: 17725559

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Project description:BACKGROUND:Various transcription factors are involved in the process of mutually exclusive expression and clonal variation of the Plasmodium multigene (var) family. Recent studies revealed that a P. falciparum SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (PfSWIB) might trigger stage-specific programmed cell death (PCD), and was not only crucial for the survival and development of parasite, but also had profound effects on the parasite by interacting with other unknown proteins. However, it remains unclear whether PfSIWB is involved in transcriptional regulation of this virulence gene and its functional properties. METHODS:A conditional knockdown system "PfSWIB-FKBP-LID" was introduced to the parasite clone 3D7, and an integrated parasite line "PfSWIB-HA-FKBP-LID" was obtained by drug cycling and clone screening. Growth curve analysis (GCA) was performed to investigate the growth and development of different parasite lines during 96 h in vitro culturing, by assessing parasitemia. Finally, we performed qPCR assays to detect var gene expression profiling in various comparison groups, as well as the mutually exclusive expression pattern of the var genes within a single 48 h life-cycle of P. falciparum in different parasite lines. In addition, RNA-seq was applied to analyze the var gene expression in different lines. RESULTS:GCA revealed that conditional knockdown of PfSWIB could interfere with the growth and development of P. falciparum. The parasitemia of PfSWIB∆ showed a significant decline at 96 h during in vitro culture compared with the PfSWIB and 3D7 lines (P < 0.0001). qPCR and RNA-seq analysis confirmed that depletion of PfSWIB not only silences upsA, upsC and partial upsB var genes, as well as removes the silencing of partial upsB var genes at the ring stage in PfSWIB∆ line, but also leads to aberrant expression of upsA and partial upsB/upsC var genes at the mature stage of P. falciparum, during a single 48-h life-cycle. CONCLUSIONS:We demonstrated that PfSWIB was involved in the process of clonal variation in var gene expression, and crucial for the survival and development of Plasmodium parasite. These findings could provide better understanding of the mechanism and function of PfSWIB contributing to the pathogenesis in malaria parasites.

Dataset Information

Alterations in local chromatin environment are involved in silencing and activation of subtelomeric var genes in Plasmodium falciparum.

Publications

Alterations in local chromatin environment are involved in silencing and activation of subtelomeric var genes in Plasmodium falciparum.

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