PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum.
PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum.
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PfSETvs 组蛋白 H3K36 甲基化抑制恶性疟原虫毒力基因
DOI：
10.1038/nature12361
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发表时间：
2013-07-11
期刊：
影响因子：
64.8
通讯作者：
Miller, Louis H.
中科院分区：
文献类型：
--
作者：
Jiang, Lubin;Mu, Jianbing;Zhang, Qingfeng;Ni, Ting;Srinivasan, Prakash;Rayavara, Kempaiah;Yang, Wenjing;Turner, Louise;Lavstsen, Thomas;Theander, Thor G.;Peng, Weiqun;Wei, Guiying;Jing, Qingqing;Wakabayashi, Yoshiyuki;Bansal, Abhisheka;Luo, Yan;Ribeiro, Jose M. C.;Scherf, Artur;Aravind, L.;Zhu, Jun;Zhao, Keji;Miller, Louis H.
恶性疟原虫红细胞膜蛋白1(PfEMP1)是表达于恶性疟原虫感染红细胞表面的变异型抗原，是疟疾的重要致病因子。每种寄生虫都有60个抗原性不同的var基因，每个基因编码不同的PfEMP1蛋白。在感染期间，克隆寄生虫群体一次只表达一个基因，然后切换到表达新的变异抗原作为一种免疫逃避机制，以避免宿主抗体反应。60个var基因中的59个被沉默的机制在很大程度上仍不清楚。在这里，我们发现敲除恶性疟原虫变异体沉默集基因(这里称为PfSETvs)，导致几乎所有的var基因在单个寄生虫核中转录，并以蛋白质的形式在单个感染的红细胞表面表达。依赖于PfSETvs的H3K36me3存在于整个基因体，包括转录起始点，以沉默var基因。由于PfSETv在var基因转录起始点和内含子启动子上的占有率较低，var基因的表达与其相应的反义长非编码RNA的转录一致。这些结果揭示了PfSETvs依赖的H3K36me3在恶性疟原虫var基因沉默中的未知作用，这可能提供了PfSETvs的同源基因抑制其他真核细胞中基因表达的一般机制。表达全部PfEMP1蛋白的PfSETvs基因敲除寄生虫也可用于疟疾疫苗的研制。
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.
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影响因子：
4.5
作者：
Rechtsteiner A;Ercan S;Takasaki T;Phippen TM;Egelhofer TA;Wang W;Kimura H;Lieb JD;Strome S
通讯作者：
Strome S
DOI：
10.1038/nrmicro2145
发表时间：
2009-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Chan, Jo-Anne;Howell, Katherine B.;Beeson, James G.
通讯作者：
Beeson, James G.
影响因子：
9.8
作者：
Tonkin CJ;Carret CK;Duraisingh MT;Voss TS;Ralph SA;Hommel M;Duffy MF;Silva LM;Scherf A;Ivens A;Speed TP;Beeson JG;Cowman AF
通讯作者：
Cowman AF
影响因子：
6.7
作者：
Joergensen L;Bengtsson DC;Bengtsson A;Ronander E;Berger SS;Turner L;Dalgaard MB;Cham GK;Victor ME;Lavstsen T;Theander TG;Arnot DE;Jensen AT
通讯作者：
Jensen AT