Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA.
Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA.
Nat Commun. 2023 Aug 22;14(1):5086. doi: 10.1038/s41467-023-40883-w.
The complex life cycle of Plasmodium falciparum requires coordinated gene expression regulation to allow host cell invasion, transmission, and immune evasion. Increasing evidence now suggests a major role for epigenetic mechanisms in gene expression in the parasite. In eukaryotes, many lncRNAs have been identified to be pivotal regulators of genome structure and gene expression. To investigate the regulatory roles of lncRNAs in P. falciparum we explore the intergenic lncRNA distribution in nuclear and cytoplasmic subcellular locations. Using nascent RNA expression profiles, we identify a total of 1768 lncRNAs, of which 718 (~41%) are novels in P. falciparum. The subcellular localization and stage-specific expression of several putative lncRNAs are validated using RNA-FISH. Additionally, the genome-wide occupancy of several candidate nuclear lncRNAs is explored using ChIRP. The results reveal that lncRNA occupancy sites are focal and sequence-specific with a particular enrichment for several parasite-specific gene families, including those involved in pathogenesis and sexual differentiation. Genomic and phenotypic analysis of one specific lncRNA demonstrate its importance in sexual differentiation and reproduction. Our findings bring a new level of insight into the role of lncRNAs in pathogenicity, gene regulation and sexual differentiation, opening new avenues for targeted therapeutic strategies against the deadly malaria parasite.
疟原虫复杂的生命周期需要协调基因表达调控，以允许宿主细胞入侵、传播和免疫逃避。越来越多的证据表明，表观遗传机制在寄生虫中的基因表达中起着重要作用。在真核生物中，已经鉴定出许多 lncRNA 是基因组结构和基因表达的关键调节剂。为了研究 lncRNA 在疟原虫中的调控作用，我们探索了核和细胞质亚细胞位置中的基因间 lncRNA 分布。使用新生 RNA 表达谱，我们总共鉴定出 1768 个 lncRNA，其中 718 个（约 41%）在疟原虫中是新的。使用 RNA-FISH 验证了几个假定 lncRNA 的亚细胞定位和阶段特异性表达。此外，还使用 ChIRP 探索了几个候选核 lncRNA 的全基因组占有率。结果表明，lncRNA 占据位点是焦点和序列特异性的，特别是对几种寄生虫特异性基因家族具有特别丰富的占有率，包括那些与发病机制和性分化有关的基因家族。对一个特定 lncRNA 的基因组和表型分析表明，它在性分化和繁殖中具有重要作用。我们的发现为 lncRNA 在致病性、基因调控和性分化中的作用提供了新的见解，为针对致命疟原虫的靶向治疗策略开辟了新的途径。
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