A transcriptional switch underlies commitment to sexual development in malaria parasites.
A transcriptional switch underlies commitment to sexual development in malaria parasites.
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许多寄生虫的生命周期涉及不同宿主物种之间的过渡，需要这些寄生虫经历多个发育阶段，以适应这些专门的小生境。疟疾寄生虫（Plasmodium spp.）从人类到蚊子载体需要从在红细胞内复制的无性阶段分化为不分裂的雄性和雌性配子体。虽然配子体在1880年首次被描述，但我们对配子体形成的分子机制的理解非常有限，破坏这一关键的发育过渡仍然是一个长期的目标。我们发现DNA结合蛋白PfAP 2-G的表达水平与配子体形成水平密切相关。使用独立的正向和反向遗传学方法，我们证明PfAP2-G功能是必不可少的寄生虫性分化。通过将全基因组PfAP2-G同源基序的发生与PfAP2-G消融导致的全局转录变化相结合，我们将早期配子体基因鉴定为PfAP2-G的可能靶点，并表明PfAP2-G对其的调控对其野生型水平表达至关重要。在无性血液阶段的寄生虫中，pfap2-g似乎是一组表观遗传沉默的基因座，易于自发激活。随机激活提出了一个简单的机制，低基线的配子体生产。总的来说，这些研究结果确定PfAP2-G作为疟疾寄生虫性阶段发育的主要调节因子，并标志着首次确定控制原生动物寄生虫分化决定的转录开关。
The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited and disrupting this critical developmental transition remains a long-standing goal. We show here that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as likely targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci prone to spontaneous activation. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first identification of a transcriptional switch controlling a differentiation decision in protozoan parasites.
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