Mammalian genomes host a diverse array of RNA that includes protein-coding and noncoding transcripts. However, the functional roles of most long noncoding RNAs (lncRNAs) remain elusive. Using RNA-targeting CRISPR-Cas13 screens, we probed how the loss of ∼6,200 lncRNAs impacts cell fitness across five human cell lines and identified 778 lncRNAs with context-specific or broad essentiality. We confirm their essentiality with individual perturbations and find that the majority of essential lncRNAs operate independently of their nearest protein-coding genes. Using transcriptome profiling in single cells, we discover that the loss of essential lncRNAs impairs cell-cycle progression and drives apoptosis. Many essential lncRNAs demonstrate dynamic expression across tissues during development. Using ∼9,000 primary tumors, we pinpoint those lncRNAs whose expression in tumors correlates with survival, yielding new biomarkers and potential therapeutic targets. This transcriptome-wide survey of functional lncRNAs advances our understanding of noncoding transcripts and demonstrates the potential of transcriptome-scale noncoding screens with Cas13.

中文翻译：

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转录组规模的 RNA 靶向 CRISPR 筛选揭示了人类细胞中必需的 lncRNA


哺乳动物基因组承载着多种 RNA，包括蛋白质编码和非编码转录本。然而，大多数长链非编码 RNA （lncRNA） 的功能作用仍然难以捉摸。使用靶向 RNA 的 CRISPR-Cas13 筛选，我们探测了 ∼6,200 个 lncRNA 的丢失如何影响五种人类细胞系的细胞适应性，并鉴定了 778 个具有上下文特异性或广泛必需性的 lncRNA。我们通过单独的扰动证实了它们的重要性，并发现大多数必需的 lncRNA 独立于其最近的蛋白质编码基因发挥作用。使用单细胞中的转录组分析，我们发现必需 lncRNA 的丢失会损害细胞周期进程并驱动细胞凋亡。许多必需的 lncRNA 在发育过程中表现出跨组织的动态表达。使用 ∼9,000 个原发性肿瘤，我们确定了那些在肿瘤中表达与生存相关的 lncRNA，从而产生新的生物标志物和潜在的治疗靶点。这种功能性 lncRNA 的转录组范围调查促进了我们对非编码转录本的理解，并展示了 Cas13 转录组规模非编码筛选的潜力。