Ukaegbu Uchechi E, Zhang Xu, Heinberg Adina R, Wele Mamadou, Chen Qijun, Deitsch Kirk W
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America.
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, United States of America; Key Laboratory of Zoonosis, College of Veterinary Medicine, Jilin University, Xi An Da Lu, Changchun, China.
PLoS Genet. 2015 May 19;11(5):e1005234. doi: 10.1371/journal.pgen.1005234. eCollection 2015 May.
Mutually exclusive gene expression, whereby only one member of a multi-gene family is selected for activation, is used by the malaria parasite Plasmodium falciparum to escape the human immune system and perpetuate long-term, chronic infections. A family of genes called var encodes the chief antigenic and virulence determinant of P. falciparum malaria. var genes are transcribed in a mutually exclusive manner, with switching between active genes resulting in antigenic variation. While recent work has shed considerable light on the epigenetic basis for var gene activation and silencing, how switching is controlled remains a mystery. In particular, switching seems not to be random, but instead appears to be coordinated to result in timely activation of individual genes leading to sequential waves of antigenically distinct parasite populations. The molecular basis for this apparent coordination is unknown. Here we show that var2csa, an unusual and highly conserved var gene, occupies a unique position within the var gene switching hierarchy. Induction of switching through the destabilization of var specific chromatin using both genetic and chemical methods repeatedly led to the rapid and exclusive activation of var2csa. Additional experiments demonstrated that these represent "true" switching events and not simply de-silencing of the var2csa promoter, and that activation is limited to the unique locus on chromosome 12. Combined with translational repression of var2csa transcripts, frequent "default" switching to this locus and detection of var2csa untranslated transcripts in non-pregnant individuals, these data suggest that var2csa could play a central role in coordinating switching, fulfilling a prediction made by mathematical models derived from population switching patterns. These studies provide the first insights into the mechanisms by which var gene switching is coordinated as well as an example of how a pharmacological agent can disrupt antigenic variation in Plasmodium falciparum.
相互排斥的基因表达，即多基因家族中只有一个成员被选择激活，被恶性疟原虫用来逃避人类免疫系统并维持长期的慢性感染。一个名为var的基因家族编码恶性疟原虫疟疾的主要抗原和毒力决定因素。var基因以相互排斥的方式转录，活性基因之间的转换导致抗原变异。虽然最近的研究对var基因激活和沉默的表观遗传基础有了相当多的了解，但转换是如何被控制的仍然是个谜。特别是，转换似乎不是随机的，而是似乎被协调以导致单个基因的及时激活，从而产生抗原性不同的寄生虫群体的连续波。这种明显协调的分子基础尚不清楚。在这里，我们表明var2csa是一个不寻常且高度保守的var基因，在var基因转换层次结构中占据独特位置。使用遗传和化学方法通过破坏var特异性染色质的稳定性来诱导转换，反复导致var2csa的快速和特异性激活。进一步的实验表明，这些代表“真正的”转换事件，而不仅仅是var2csa启动子的去沉默，并且激活仅限于12号染色体上的独特位点。结合var2csa转录本的翻译抑制、频繁“默认”转换到该位点以及在非孕妇个体中检测到var2csa未翻译的转录本，这些数据表明var2csa可能在协调转换中发挥核心作用，实现了从群体转换模式推导的数学模型所做出的预测。这些研究首次深入了解了var基因转换是如何被协调的，以及一种药物制剂如何破坏恶性疟原虫的抗原变异的实例。
