Global transcriptional repression: An initial and essential step for Plasmodium sexual development
Global transcriptional repression: An initial and essential step for Plasmodium sexual development
复制标题
DOI：
10.1073/pnas.1504389112
复制
发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
M. Yuda;S. Iwanaga;Izumi Kaneko;Tomomi Kato
中科院分区：
文献类型：
--
作者：
M. Yuda;S. Iwanaga;Izumi Kaneko;Tomomi Kato
### 意义
在疟原虫中，配子体形成是一个从无性血液期寄生虫产生配子体（配子的前体）的过程。在本研究中，我们报告称疟原虫转录抑制因子 AP2 - G2 在这一过程中发挥着至关重要的作用。我们发现，AP2 - G2 抑制无性阶段增殖所需的基因，从而促进从无性血液期向非复制性有性阶段的转变。同样，在后生动物（包括昆虫）生殖系形成的初始阶段，一种主转录抑制因子会在胚胎细胞中确定原始生殖细胞。因此，我们的研究结果表明，尽管真核生物在进化上存在差异，但建立生殖系所需的基本分子机制在真核生物中是保守的。
配子体是介导疟疾传播给蚊子媒介的非复制性有性形式。它们由在血液循环中增殖的无性血液期寄生虫产生。然而，对于这一转变在基因层面是如何调控的，人们知之甚少。在此，我们报告一种 Apetala2（AP2）家族转录因子 AP2 - G2 作为转录抑制因子调控这一转变。在啮齿动物疟原虫伯氏疟原虫中破坏 AP2 - G2 并不会阻止向有性阶段的转变，但会在性别特异性形态出现之前停止发育。染色质免疫沉淀测序（ChIP - seq）分析显示，AP2 - G2 靶向约 1500 个基因，并识别其启动子中的一个五碱基基序。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 阻断了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，所确定的靶基因约占 AP2 - G2 缺失的寄生虫中上调基因的 70%，这表明 AP2 - G2 在配子体中实际上起着抑制因子的作用。使用着丝粒质粒进行的启动子分析表明，该结合基序作为一种顺式作用负调控元件发挥作用。这些结果表明，在配子体形成初始阶段发生的全局转录抑制是疟原虫有性发育的一个关键步骤。
Significance In malaria parasites, gametocytogenesis is a process whereby gametocytes, the precursors of gametes, are generated from asexual blood-stage parasites. In this study, we report that the plasmodium transcriptional repressor AP2-G2 plays an essential role in this process. We found that AP2-G2 represses the genes that are required for the proliferation of the asexual stage and, thereby, supports the conversion from the asexual blood stage to the nonreplicative sexual stage. Similarly, during the initial phase of germ-line formation in metazoan animals (including insects), a master transcriptional repressor specifies primordial germ cells among embryonic cells. Thus, our findings suggest that the basic molecular mechanisms that are required to establish the germ line have been conserved in eukaryotes, despite their evolutionary divergence. 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.