Rrp6 Regulates Heterochromatic Gene Silencing via ncRNA RUF6 Decay in Malaria Parasites
Rrp6 Regulates Heterochromatic Gene Silencing via ncRNA RUF6 Decay in Malaria Parasites
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Rrp6 通过疟原虫中的 ncRNA RUF6 衰变调节异染色质基因沉默。
DOI：
10.1128/mbio.01110-20
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发表时间：
2020-05-01
期刊：
影响因子：
6.4
通讯作者：
Zhang，Qingfeng
中科院分区：
文献类型：
--
作者：
Fan，Yanting;Shen，Shijun;Zhang，Qingfeng
异染色质环境在沉默与疟疾寄生虫的发育、在宿主中生存以及向蚊子媒介传播相关的基因方面发挥着核心作用。然而，调节动态染色质结构的潜在机制尚不清楚。在这里，我们发现恶性疟原虫 Rrp6（真核 RNA 外泌体相关 RNase 的直系同源物）控制异染色质基因的沉默。 PfRrp6 敲低通过稳定新生转录本，破坏了富含 GC 的 ncRNA RUF6 家族的单一表达，RUF6 家族是毒力基因表达的已知关键调节因子。机制研究表明，多个 RUF6 ncRNA 的积累触发了局部染色质原位重塑，从而激活了相邻的变异基因。引人注目的是，通过 RNA 纯化分析 (ChIRP-seq) 进行的染色质分离揭示了一种显着的 RUF6 ncRNA 与远端异染色质区域直接相互作用，并刺激了对异染色质基因的整体去抑制作用，包括所有变异基因家族和性承诺相关的regulatorap2-g基因。总的来说，Rrp6 似乎通过控制 RUF6 水平对异染色质基因表达进行表观遗传监测，从而确保宿主感染期间疟疾寄生虫的抗原变异和性承诺。重要性疟疾仍然是主要的公共卫生和经济负担。异染色质环境控制与疟原虫命运相关的基因沉默。先前的研究表明，一组富含GC的ncRNA（RUF6）与vargenes的互斥表达相关，但潜在的机制仍然难以捉摸。在这里，通过一系列的遗传操作和全基因组多组学分析，我们确定了RNA外泌体相关Rrp6的疟原虫直系同源物作为RUF6表达的上游调节因子，并揭示了Rrp6敲低后RUF6的失调触发了局部染色质改变，从而通过RUF6和远端基因位点的直接相互作用激活大多数异染色质基因。这一发现不仅揭示了RUF6介导的异染色质基因调控的深层机制，而且确定了Rrp6作为人类疟原虫基因表达的新型调节因子，为制定针对疟疾的干预策略提供了新的靶点。
The heterochromatin environment plays a central role in silencing genes associated with the malaria parasite’s development, survival in the host, and transmission to the mosquito vector. However, the underlying mechanism regulating the dynamic chromatin structure is not understood yet. Here, we have uncovered that Plasmodium falciparum Rrp6, an orthologue of eukaryotic RNA exosome-associated RNase, controls the silencing of heterochromatic genes. PfRrp6 knockdown disrupted the singular expression of the GC-rich ncRNA RUF6 family, a known critical regulator of virulence gene expression, through the stabilization of the nascent transcripts. Mechanistic investigation showed that the accumulation of the multiple RUF6 ncRNAs triggered local chromatin remodelingin situ, which activated their adjacentvargenes. Strikingly, chromatin isolation by RNA purification analysis (ChIRP-seq) revealed that a remarkable RUF6 ncRNA had interacted with distal heterochromatin regions directly and stimulated a global derepression effect on heterochromatic genes, including all variant gene families and the sexual commitment-associated regulatorap2-ggene. Collectively, Rrp6 appears to conduct the epigenetic surveillance of heterochromatic gene expression through controlling RUF6 levels, thereby securing antigenic variation and sexual commitment of malaria parasites during the infection of the host.IMPORTANCEMalaria remains a major public health and economic burden. The heterochromatin environment controls the silencing of genes associated with the fate of malaria parasites. Previous studies have demonstrated that a group of GC-rich ncRNAs (RUF6) is associated with the mutually exclusive expression ofvargenes, but the underlying mechanisms remain elusive. Here, through a series of genetic manipulation and genome-wide multiomics analysis, we have identified the plasmodial orthologue of RNA exosome-associated Rrp6 as an upstream regulator of RUF6 expression and revealed that the dysregulation of RUF6 upon Rrp6 knockdown triggered local chromatin alteration, thereby activating most heterochromatic genes via direct interaction of RUF6 and distal gene loci. This finding not only uncovered the in-depth mechanism of RUF6-mediated regulation of heterochromatic genes but also identified Rrp6 as a novel regulator of gene expression in human malaria parasites, which provides a new target for developing intervention strategies against malaria.