Active transcription is required for maintenance of epigenetic memory in the malaria parasite Plasmodium falciparum.
Active transcription is required for maintenance of epigenetic memory in the malaria parasite Plasmodium falciparum.
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DOI：
10.1016/j.jmb.2008.07.015
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发表时间：
2008-10-03
影响因子：
5.6
通讯作者：
Deitsch, Kirk W.
中科院分区：
文献类型：
--
作者：
Dzikowski, Ron;Deitsch, Kirk W.
最严重的人类疟疾是由原生动物寄生虫恶性疟原虫引起的。感染红细胞表面表达的主要抗原和毒力决定簇是PfEMP 1，这是一种介导寄生虫在深部组织血管床中粘附和隔离的蛋白质。不同形式的PfEMP 1由多拷贝var基因家族的不同成员编码。var基因的表达是相互排斥的，并且通过转换哪个基因被表达，寄生虫改变它们的抗原和毒力表型。var基因表达的调控涉及基因激活、沉默和细胞记忆，控制这一过程的机制细节尚不清楚。在这里，我们提供的证据表明，需要主动转录的细胞记忆的维护，标志着一个特定的var基因在许多细胞周期中稳定表达。迫使转染的寄生虫表达越来越多的不受调节的附加型var启动子导致相应的下调的活性var基因在寄生虫的基因组中，大概是通过竞争的寄生虫的转录机制，并建议存在一个有限的核因子，这是需要var基因激活。这个过程使我们能够抑制活性var基因的转录，而不通过控制互斥表达的机制起作用，从而研究转录本身在维持表观遗传记忆中的作用。当竞争的附加体被移除时，寄生虫并没有恢复到它们先前的var基因表达模式，而是显示出随机的var基因激活，这表明控制var基因表达的表观遗传印记已经被完全清除，从而将活性转录与细胞记忆的维持联系起来。
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, 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 multi-copy 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.
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影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
64.5
作者：
BARUCH, DI;PASLOSKE, BL;HOWARD, RJ
通讯作者：
HOWARD, RJ
影响因子：
4.8
作者：
Calderwood, MS;Gannoun-Zaki, L;Deitsch, KW
通讯作者：
Deitsch, KW
影响因子：
11.4
作者：
Scherf, A;Hernandez-Rivas, R;Lanzer, M
通讯作者：
Lanzer, M
影响因子：
3.6
作者：
Kraemer, SM;Smith, JD
通讯作者：
Smith, JD