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Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites

机译：单细胞RNA测序揭示了疟疾寄生虫中性承诺的特征

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摘要

Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes(1). Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite and ends, 48 hours later, with a schizont releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes(2,3). Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600)(4,5), the master regulator of sexual development, from an epigenetically silenced state during asexual replication(6,7). AP2-G expression during this 'commitment cycle' prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism(2,4). To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1-30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling(8). Here we use highly parallel, single-cell RNA sequencing(9) of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G(+) mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histonemodifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.
机译：病原体必须平衡传播与持久性。对于恶性疟原虫而言，疟原虫是最广泛和最致命的疟疾寄生虫，要在其人类宿主中持续存在，就必须在红血球中持续无性繁殖，而其蚊媒传播取决于红细胞内的分化为非复制性阶段，称为配子体（1）。在前一个细胞周期中确定对任何一种命运的承诺，该周期从单个无性定殖裂殖子的侵袭开始，到48小时后裂殖体释放新形成的裂殖子，全部致力于持续无性繁殖或分化成配子细胞（2）。 ，3）。性承诺需要从无性繁殖过程中的表观遗传沉默状态激活ap2-g（PF3D7_1222600）（4,5）的转录激活，这是性发育的主要调节因子。在这个``承诺周期''中，AP2-G的表达使新生裂殖子中的基因表达得以准备，从而通过迄今未知的机制引发性发育（2,4）。为了维持持续的感染，ap2-g的表达仅限于寄生虫亚群（1-30％，取决于遗传背景和生长条件）。由于有性承诺的裂殖体仅包含一个亚群，并且在形态上与无性承诺的裂殖体没有区别，因此使用传统的大量转录组分析很难确定其特征性基因表达（8）。在这里，我们使用高度平行的单细胞RNA测序（9）进行有性承诺的疟疾文化，以确定该亚群中AP2-G诱导的转录变化。通过分析来自多个发育阶段的条件性AP2-G敲除品系和NF54野生型寄生虫的18,000多个单个寄生虫转录组，我们显示，具有性行为的AP2-G（+）成熟裂殖体特别上调了基因表达的其他调节剂，包括其他AP2转录因子，组蛋白修饰酶和核小体定位调节剂。这些表观遗传调节剂可以起到促进表达和/或抑制在随后的细胞周期中启动配子细胞发育所必需的基因的作用。

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  • 来源
    《Nature》 |2017年第7678期|95-99|共5页
  • 作者

    Poran Asaf; Notzel Christopher; Aly Omar; Mencia-Trinchant Nuria; Harris Chantal T.; Guzman Monica L.; Hassane Duane C.; Lemento Olivier E.; Kafsack Bjorn F. C.;

  • 作者单位

    Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA|Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10065 USA|Weill Cornell Med, Physiol Biophys & Syst Biol Grad Program, New York, NY 10065 USA;

    Weill Cornell Med, Biochem Cell & Mol Biol Grad Program, New York, NY 10065 USA|Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA;

    Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA|Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10065 USA;

    Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY 10065 USA;

    Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA|Weill Cornell Med, Immunol & Microbial Pathogenesis Grad Program, New York, NY 10065 USA;

    Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY 10065 USA;

    Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA|Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY 10065 USA;

    Weill Cornell Med, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA|Weill Cornell Med, Caryl & Israel Englander Inst Precis Med, New York, NY 10065 USA;

    Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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