Lopez-Rubio Jose Juan, Gontijo Alisson M, Nunes Marta C, Issar Neha, Hernandez Rivas Rosaura, Scherf Artur
Institut Pasteur-CNRS, 25 rue du Dr Roux, 75724 Paris, France.
Mol Microbiol. 2007 Dec;66(6):1296-305. doi: 10.1111/j.1365-2958.2007.06009.x. Epub 2007 Nov 19.
In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long-term chronic infection of the host. This is achieved by sequential expression of a single member of the 60-member var family. Here we show that the 5' flanking region nucleates epigenetic events strongly linked to the maintenance of mono-allelic var gene expression pattern during parasite proliferation. Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.
在人类疟原虫恶性疟原虫中，抗原变异有助于宿主的长期慢性感染。这是通过60个成员的var家族中单个成员的顺序表达来实现的。在这里，我们表明5'侧翼区域引发了与寄生虫增殖过程中var基因单等位基因表达模式维持密切相关的表观遗传事件。组蛋白H3赖氨酸4的三甲基化和二甲基化在转录的var基因的5'上游区域以及准备状态（在48小时无性生命周期中var基因的非转录阶段）达到峰值，“标记”该成员以便在下一个周期开始时重新激活。组蛋白H3赖氨酸9三甲基化作为赖氨酸4甲基化的拮抗剂，在5'侧翼和编码区域建立稳定沉默的var基因状态。此外，我们表明在5'侧翼区域H3K9甲基化和H3K9乙酰化之间存在竞争，并且这些标记在表观遗传上有助于抑制或激活var基因表达。我们的工作指出了组蛋白甲基标记写入和读取机制在疟原虫毒力性状表型遗传中的关键作用。
