College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
BGI-Shenzhen, Shenzhen, 518083, China.
Sci Rep. 2023 Jun 26;13(1):10335. doi: 10.1038/s41598-023-37325-4.
RNA editing is a post-transcriptional modification with a cell-specific manner and important biological implications. Although single-cell RNA-seq (scRNA-seq) is an effective method for studying cellular heterogeneity, it is difficult to detect and study RNA editing events from scRNA-seq data because of the low sequencing coverage. To overcome this, we develop a computational method to systematically identify RNA editing sites of cell types from scRNA-seq data. To demonstrate its effectiveness, we apply it to scRNA-seq data of human hematopoietic stem/progenitor cells (HSPCs) with an annotated lineage differentiation relationship according to previous research and study the impacts of RNA editing on hematopoiesis. The dynamic editing patterns reveal the relevance of RNA editing on different HSPCs. For example, four microRNA (miRNA) target sites on 3' UTR of EIF2AK2 are edited across all HSPC populations, which may abolish the miRNA-mediated inhibition of EIF2AK2. Elevated EIF2AK2 may thus activate the integrated stress response (ISR) pathway to initiate global translational attenuation as a protective mechanism to maintain cellular homeostasis during HSPCs' differentiation. Besides, our findings also indicate that RNA editing plays an essential role in the coordination of lineage commitment and self-renewal of hematopoietic stem cells (HSCs). Taken together, we demonstrate the capacity of scRNA-seq data to exploit RNA editing events of cell types, and find that RNA editing may exert multiple modules of regulation in hematopoietic processes.
RNA 编辑是一种具有细胞特异性的转录后修饰,具有重要的生物学意义。虽然单细胞 RNA 测序 (scRNA-seq) 是研究细胞异质性的有效方法,但由于测序覆盖度低,很难从 scRNA-seq 数据中检测和研究 RNA 编辑事件。为了克服这一问题,我们开发了一种计算方法,用于从 scRNA-seq 数据中系统地鉴定细胞类型的 RNA 编辑位点。为了证明其有效性,我们将其应用于人类造血干细胞/祖细胞 (HSPCs) 的 scRNA-seq 数据,这些数据根据先前的研究具有注释的谱系分化关系,并研究 RNA 编辑对造血的影响。动态编辑模式揭示了 RNA 编辑在不同 HSPC 中的相关性。例如,EIF2AK2 3'UTR 上的四个 microRNA (miRNA) 靶位点在所有 HSPC 群体中都被编辑,这可能会消除 miRNA 对 EIF2AK2 的抑制作用。因此,EIF2AK2 的升高可能会激活整合应激反应 (ISR) 途径,启动全局翻译衰减,作为 HSPC 分化过程中维持细胞内稳态的保护机制。此外,我们的研究结果还表明,RNA 编辑在谱系分化和造血干细胞 (HSCs) 自我更新的协调中起着至关重要的作用。总之,我们证明了 scRNA-seq 数据能够挖掘细胞类型的 RNA 编辑事件,并发现 RNA 编辑可能在造血过程中发挥多个调控模块的作用。