A cascade of transcriptional repression determines sexual commitment and development in Plasmodium falciparum.
A cascade of transcriptional repression determines sexual commitment and development in Plasmodium falciparum.
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一系列转录抑制决定恶性疟原虫的性承诺和发育
DOI：
10.1093/nar/gkab683
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发表时间：
2021-09-20
影响因子：
14.9
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Shang X;Shen S;Tang J;He X;Zhao Y;Wang C;He X;Guo G;Liu M;Wang L;Zhu Q;Yang G;Jiang C;Zhang M;Yu X;Han J;Culleton R;Jiang L;Cao J;Gu L;Zhang Q
配子细胞发生是疟疾寄生虫产生可感染蚊子的有性形式的过程，它对疟疾的传播至关重要。pfap2-g基因的转录开关触发了性承诺，但这个复杂的多步骤过程是如何精确编程的，在很大程度上仍然未知。在这里，通过对一组ApiAP2转录因子的系统功能筛选，我们确定了6个与恶性疟原虫配子细胞发生相关的ApiAP2新成员。其中PfAP2-G5 （PF3D7_1139300）在配子细胞发生中是不可缺少的。该因子通过结合上游区域和外显子基因体来抑制pfap2-g基因的转录活性，后者与维持局部异染色质结构有关，从而阻止性承诺的开始。通过敲除pfap2-g5来去除这种抑制作用，破坏无性复制周期，促进性承诺，同时上调pfap2-g的表达。然而，产生的配子体不能完全成熟。进一步分析表明，PfAP2-G5对配子细胞成熟至关重要，并在配子细胞发育之前导致pfap2-g和一组由pfap2-g激活的早期配子细胞基因的下调。总的来说，我们的发现揭示了疟原虫配子体产生的调控级联，并为传播阻断干预提供了新的靶点。
Gametocytogenesis, the process by which malaria parasites produce sexual forms that can infect mosquitoes, is essential for the transmission of malaria. A transcriptional switch of the pfap2-g gene triggers sexual commitment, but how the complex multi-step process is precisely programed remains largely unknown. Here, by systematic functional screening of a panel of ApiAP2 transcription factors, we identify six new ApiAP2 members associated with gametocytogenesis in Plasmodium falciparum. Among these, PfAP2-G5 (PF3D7_1139300) was found to be indispensable for gametocytogenesis. This factor suppresses the transcriptional activity of the pfap2-g gene via binding to both the upstream region and exonic gene body, the latter is linked to the maintenance of local heterochromatin structure, thereby preventing initiation of sexual commitment. Removal of this repressive effect through pfap2-g5 knockout disrupts the asexual replication cycle and promotes sexual commitment accompanied by upregulation of pfap2-g expression. However, the gametocytes produced fail to mature fully. Further analyses show that PfAP2-G5 is essential for gametocyte maturation, and causes the down-regulation of pfap2-g and a set of early gametocyte genes activated by PfAP2-G prior to gametocyte development. Collectively, our findings reveal a regulation cascade of gametocyte production in malaria parasites, and provide a new target for transmission blocking interventions.