Genome-wide regulatory dynamics of translation in the Plasmodium falciparum asexual blood stages.
Genome-wide regulatory dynamics of translation in the Plasmodium falciparum asexual blood stages.
复制标题
DOI：
10.7554/elife.04106
复制
发表时间：
2014-12-10
期刊：
影响因子：
7.7
通讯作者：
DeRisi JL
中科院分区：
文献类型：
--
作者：
Caro F;Ahyong V;Betegon M;DeRisi JL
恶性疟原虫的转录组和蛋白质组的特性是了解这种寄生虫的分子生理学的巨大资源。然而，将稳态mRNA与蛋白质水平联系起来的翻译动力学尚未得到很好的理解。在这项研究中，我们通过使用核糖体分析测量全基因组翻译，通过恶性疟原虫血液阶段发育周期的五个阶段来弥合这种脱节。我们的研究结果表明，转录和翻译是紧密耦合的，明显的翻译控制发生不到10%的转录组。翻译调控基因主要与裂殖子排出功能相关。我们系统地定义了mRNA的5′前导序列、3′ UTR以及反义转录物，沿着每种转录物的核糖体占有率，并确定核糖体在5′前导序列上的积累是一种常见的转录物特征。这项工作代表了迄今为止这种医学上重要的寄生虫的基因表达和翻译的最高分辨率和最广泛的肖像。DOI：http://dx.doi.org/10.7554/eLife.04106.001生物体的基因组包括构建、维持和复制该生物体所需的所有基因或信息。然而，具有相同基因组的细胞例如来自同一个人的皮肤细胞和肝细胞根据它们基因组中的哪种基因表达以及表达的程度，它们的外观和行为可能非常不同。对于一个要表达的基因，它的DNA被“转录”成RNA分子，然后被“翻译”成蛋白质。测量患病细胞或引起感染的微生物中的转录和翻译过程的努力可能会带来新的治疗方法和预防药物。目前，在全球防治疟疾的努力中，正在开展这项工作。疟疾是可以预防和治愈的，但估计每年有60多万人死于这种疾病。这种疾病是由一种叫做疟原虫的单细胞寄生虫引起的。蚊子的唾液腺携带寄生虫，当蚊子叮咬人类时，这些寄生虫会随着蚊子的唾液注入血液。疟原虫寄生虫然后旅行并感染肝脏，然后从这个组织中爆发进入血液。在这里，寄生虫感染红细胞并进行多轮复制，在此期间表现出疾病的症状。也正是在这个血流阶段，寄生虫可以发展成能够感染另一只蚊子并继续传播周期的形式。恶性疟原虫是人类最严重的疟疾病原体，它的基因、RNA分子和蛋白质已经被分类，以更好地了解这种寄生虫的生物学。然而，控制RNA转录物如何以及何时翻译成蛋白质的过程还没有很好地理解。现在，Caro等人已经发现了在血液中疟原虫发育过程中，哪些RNA分子被翻译，以及翻译多少。在这种寄生虫中，基因的转录和翻译被发现是紧密相连的过程;只有少数基因的表达更多地受到翻译过程的控制，而不是转录。研究人员发现，这些受免疫调节的基因主要是那些编码蛋白质的基因，这些蛋白质参与了寄生虫从红细胞中排出并扩散到整个血液中的过程。Caro等人发现，疟原虫的基因调控类似于一个预设的基因程序，而不是一个对变化和外部信号做出反应的系统。因此，这些发现表明，针对疟原虫内的这种遗传程序并阻止其实施可能是遏制疟疾传播的有效策略。DOI：http://dx.doi.org/10.7554/eLife.04106.002网站
The characterization of the transcriptome and proteome of Plasmodium falciparum has been a tremendous resource for the understanding of the molecular physiology of this parasite. However, the translational dynamics that link steady-state mRNA with protein levels are not well understood. In this study, we bridge this disconnect by measuring genome-wide translation using ribosome profiling, through five stages of the P. falciparum blood phase developmental cycle. Our findings show that transcription and translation are tightly coupled, with overt translational control occurring for less than 10% of the transcriptome. Translationally regulated genes are predominantly associated with merozoite egress functions. We systematically define mRNA 5′ leader sequences, and 3′ UTRs, as well as antisense transcripts, along with ribosome occupancy for each, and establish that accumulation of ribosomes on 5′ leaders is a common transcript feature. This work represents the highest resolution and broadest portrait of gene expression and translation to date for this medically important parasite. DOI: http://dx.doi.org/10.7554/eLife.04106.001 The genome of an organism includes all of the genes or information necessary to build, maintain, and replicate that organism. However, cells with the same genome—such as a skin cell and a liver cell from the same person—can look and behave very differently depending on which of the genes in their genomes they express, and to what extent. For a gene to be expressed, its DNA is ‘transcribed’ to make an RNA molecule, which is then ‘translated’ to make a protein. Efforts to measure the transcription and translation processes in diseased cells, or in the microorganisms that cause infections, may lead to new treatments and preventative medicines. Such work is currently ongoing in the global effort to treat and prevent malaria. Malaria is both preventable and curable, yet over 600,000 people are estimated to die from this disease each year. The disease is caused by a single-celled parasite called Plasmodium. Mosquitoes carry the parasites in their salivary glands, and when a mosquito bites a human, these parasites are injected into the bloodstream with the mosquito's saliva. Plasmodium parasites then travel to and infect the liver, before bursting out of this tissue into the bloodstream. Here, the parasites infect red blood cells and undergo rounds of replication during which the symptoms of the disease are manifested. It is also during this bloodstream phase that parasites can develop into forms capable of infecting another mosquito and continuing the transmission cycle. The genes, RNA molecules, and proteins of the Plasmodium falciparum parasite—which causes the most serious cases of malaria in humans—have been cataloged to better understand the biology of this parasite. However, the processes that control how, and when, an RNA transcript is translated into a protein are not well understood. Now Caro et al. have uncovered which RNA molecules are being translated, and by how much, during Plasmodium development within the blood. The transcription and translation of genes in this parasite were found to be tightly linked processes; the expression of only a few genes was controlled more by the translation process than by transcription. These translationally regulated genes were found mainly to be those that encode proteins involved in the parasite's exit from the red blood cells and spread throughout the bloodstream. Caro et al. discovered that genetic regulation of the malaria parasite resembles a preset genetic program, rather than a system that responds to changes and external signals. As such, these findings suggest that targeting such a genetic program within Plasmodium and preventing its implementation could prove an effective strategy to curb the spread of malaria. DOI: http://dx.doi.org/10.7554/eLife.04106.002