PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum

Lubin Jiang; Jianbing Mu; Qingfeng Zhang; Ting Ni; Prakash Srinivasan; Kempaiah Rayavara; Wenjing Yang; Louise Turner; Thomas Lavstsen; Thor G Theander; Weiqun Peng; Guiying Wei; Qingqing Jing; Yoshiyuki Wakabayashi; Abhisheka Bansal; Yan Luo; José M C Ribeiro; Artur Scherf; L Aravind; Jun Zhu; Keji Zhao; Louis H Miller

doi:10.1038/nature12361

PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum

Lubin Jiang, Jianbing Mu, Qingfeng Zhang, Ting Ni, Prakash Srinivasan, Kempaiah Rayavara, Wenjing Yang, Louise Turner, Thomas Lavstsen, Thor G Theander, Weiqun Peng, Guiying Wei, Qingqing Jing, Yoshiyuki Wakabayashi, Abhisheka Bansal, Yan Luo, José M C Ribeiro, Artur Scherf, L Aravind, Jun ZhuKeji Zhao, Louis H Miller

141 Citations (Scopus)

Abstract

The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.

Original language	English
Journal	Nature
Volume	499
Issue number	7457
Pages (from-to)	223-7
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature12361
Publication status	Published - 11 Jul 2013

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Jiang, L., Mu, J., Zhang, Q., Ni, T., Srinivasan, P., Rayavara, K., Yang, W., Turner, L., Lavstsen, T., Theander, T. G., Peng, W., Wei, G., Jing, Q., Wakabayashi, Y., Bansal, A., Luo, Y., Ribeiro, J. M. C., Scherf, A., Aravind, L., ... Miller, L. H. (2013). PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature, 499(7457), 223-7. https://doi.org/10.1038/nature12361

Jiang, L, Mu, J, Zhang, Q, Ni, T, Srinivasan, P, Rayavara, K, Yang, W, Turner, L , Lavstsen, T , Theander, TG, Peng, W, Wei, G, Jing, Q, Wakabayashi, Y, Bansal, A, Luo, Y, Ribeiro, JMC, Scherf, A, Aravind, L, Zhu, J, Zhao, K & Miller, LH 2013, 'PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum', Nature, vol. 499, no. 7457, pp. 223-7. https://doi.org/10.1038/nature12361

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title = "PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum",

abstract = "The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.",

author = "Lubin Jiang and Jianbing Mu and Qingfeng Zhang and Ting Ni and Prakash Srinivasan and Kempaiah Rayavara and Wenjing Yang and Louise Turner and Thomas Lavstsen and Theander, {Thor G} and Weiqun Peng and Guiying Wei and Qingqing Jing and Yoshiyuki Wakabayashi and Abhisheka Bansal and Yan Luo and Ribeiro, {Jos{\'e} M C} and Artur Scherf and L Aravind and Jun Zhu and Keji Zhao and Miller, {Louis H}",

year = "2013",

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doi = "10.1038/nature12361",

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T1 - PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum

AU - Jiang, Lubin

AU - Mu, Jianbing

AU - Zhang, Qingfeng

AU - Ni, Ting

AU - Srinivasan, Prakash

AU - Rayavara, Kempaiah

AU - Yang, Wenjing

AU - Turner, Louise

AU - Lavstsen, Thomas

AU - Theander, Thor G

AU - Peng, Weiqun

AU - Wei, Guiying

AU - Jing, Qingqing

AU - Wakabayashi, Yoshiyuki

AU - Bansal, Abhisheka

AU - Luo, Yan

AU - Ribeiro, José M C

AU - Scherf, Artur

AU - Aravind, L

AU - Zhu, Jun

AU - Zhao, Keji

AU - Miller, Louis H

PY - 2013/7/11

Y1 - 2013/7/11

N2 - The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.

AB - The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.

U2 - 10.1038/nature12361

DO - 10.1038/nature12361

M3 - Journal article

C2 - 23823717

SN - 0028-0836

VL - 499

SP - 223

EP - 227

JO - Nature

JF - Nature

IS - 7457

ER -

PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum

Abstract

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