Yuda Masao, Iwanaga Shiroh, Kaneko Izumi, Kato Tomomi
Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan
Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12824-9. doi: 10.1073/pnas.1504389112. Epub 2015 Sep 28.
Gametocytes are nonreplicative sexual forms that mediate malaria transmission to a mosquito vector. They are generated from asexual blood-stage parasites that proliferate in the circulation. However, little is known about how this transition is genetically regulated. Here, we report that an Apetala2 (AP2) family transcription factor, AP2-G2, regulates this transition as a transcriptional repressor. Disruption of AP2-G2 in the rodent malaria parasite Plasmodium berghei did not prevent commitment to the sexual stage but did halt development before the appearance of sex-specific morphologies. ChIP-seq analysis revealed that AP2-G2 targeted ∼1,500 genes and recognized a five-base motif in their promoters. Most of these target genes are required for asexual proliferation of the parasites in the blood, suggesting that AP2-G2 blocks the program that precedes asexual replication to promote conversion to the sexual stage. Microarray analysis showed that the identified targets constituted ∼70% of the up-regulated genes in AP2-G2-depleted parasites, suggesting that AP2-G2 actually functions as a repressor in gametocytes. A promoter assay using a centromere plasmid demonstrated that the binding motif functions as a cis-acting negative regulatory element. These results suggest that global transcriptional repression, which occurs during the initial phase of gametocytogenesis, is an essential step in Plasmodium sexual development.
配子体是介导疟疾传播给蚊媒的非复制性有性形态。它们由在循环中增殖的无性血液阶段寄生虫产生。然而，关于这种转变如何受到基因调控知之甚少。在此，我们报告一种AP2（Apetala2）家族转录因子AP2-G2作为转录抑制因子调控这种转变。在啮齿动物疟原虫伯氏疟原虫中破坏AP2-G2并不阻止进入有性阶段，但确实在出现性别特异性形态之前停止发育。ChIP-seq分析表明，AP2-G2靶向约1500个基因，并在其启动子中识别一个五碱基基序。这些靶基因中的大多数是寄生虫在血液中无性增殖所必需的，这表明AP2-G2阻断无性复制之前的程序以促进向有性阶段的转变。微阵列分析表明，鉴定出的靶标占AP2-G2缺失寄生虫中上调基因的约70%，这表明AP2-G2在配子体中实际上作为一种抑制因子发挥作用。使用着丝粒质粒的启动子分析表明，该结合基序作为顺式作用负调控元件发挥作用。这些结果表明，在配子体发生初始阶段发生的全局转录抑制是疟原虫有性发育中的一个关键步骤。
