Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
Cell Microbiol. 2012 Dec;14(12):1836-48. doi: 10.1111/cmi.12004. Epub 2012 Sep 4.
Plasmodium falciparum is responsible for the most severe form of malaria in humans. Antigenic variation of P. falciparum erythrocyte membrane protein 1 leads to immune evasion and occurs through switches in mutually exclusive var gene transcription. The recent progress in Plasmodium epigenetics notwithstanding, the mechanisms by which singularity of var activation is achieved are unknown. Here, we employed a functional approach to dissect the role of var gene upstream regions in mutually exclusive activation. Besides identifying sequence elements involved in activation and initiation of transcription, we mapped a region downstream of the transcriptional start site that is required to maintain singular var gene choice. Activation of promoters lacking this sequence occurs no longer in competition with endogenous var genes. Within this region we pinpointed a sequence-specific DNA-protein interaction involving a cis-acting sequence motif that is conserved in the majority of var loci. These results suggest an important role for this interaction in mutually exclusive locus recognition. Our findings are furthermore consistent with a novel mechanism for the control of singular gene choice in eukaryotes. In addition to their importance in P. falciparum antigenic variation, our results may also help to explain similar processes in other systems.
恶性疟原虫是导致人类最严重疟疾的罪魁祸首。疟原虫红细胞膜蛋白 1 的抗原变异导致免疫逃避，这是通过相互排斥的 var 基因转录转换发生的。尽管最近在疟原虫表观遗传学方面取得了进展，但 var 激活的单一性是如何实现的机制尚不清楚。在这里，我们采用功能方法来剖析 var 基因上游区域在相互排斥激活中的作用。除了鉴定参与激活和转录起始的序列元件外，我们还绘制了转录起始位点下游的一个区域，该区域需要维持单一 var 基因选择。缺乏此序列的启动子的激活不再与内源性 var 基因竞争。在这个区域内，我们确定了一个涉及顺式作用序列基序的序列特异性 DNA-蛋白质相互作用，该基序在大多数 var 基因座中保守。这些结果表明该相互作用在相互排斥的基因座识别中具有重要作用。我们的研究结果还与真核生物中单一基因选择的新型调控机制一致。除了在疟原虫抗原变异中的重要性外，我们的研究结果还可能有助于解释其他系统中的类似过程。
