Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
Cell Rep. 2024 Jun 25;43(6):114369. doi: 10.1016/j.celrep.2024.114369. Epub 2024 Jun 14.
Epitranscriptomics represents a further layer of gene expression regulation. Specifically, N6-methyladenosine (m6A) regulates RNA maturation, stability, degradation, and translation. Regarding microRNAs (miRNAs), while it has been reported that m6A impacts their biogenesis, the functional effects on mature miRNAs remain unclear. Here, we show that m6A modification on specific miRNAs weakens their coupling to AGO2, impairs their function on target mRNAs, determines their delivery into extracellular vesicles (EVs), and provides functional information to receiving cells. Mechanistically, the intracellular functional impairment is caused by m6A-mediated inhibition of AGO2/miRNA interaction, the EV loading is favored by m6A-mediated recognition by the RNA-binding protein (RBP) hnRNPA2B1, and the EV-miRNA function in the receiving cell requires their FTO-mediated demethylation. Consequently, cells express specific miRNAs that do not impact endogenous transcripts but provide regulatory information for cell-to-cell communication. This highlights that a further level of complexity should be considered when relating cellular dynamics to specific miRNAs.
表观转录组学代表了基因表达调控的又一个层面。具体来说，N6-甲基腺苷（m6A）调节 RNA 的成熟、稳定性、降解和翻译。关于 microRNAs（miRNAs），虽然已经报道 m6A 影响它们的生物发生，但对成熟 miRNAs 的功能影响仍不清楚。在这里，我们表明 m6A 修饰特定的 miRNAs 会削弱它们与 AGO2 的结合，损害它们对靶 mRNA 的功能，决定它们进入细胞外囊泡（EVs），并为接收细胞提供功能信息。在机制上，m6A 介导的 AGO2/miRNA 相互作用抑制导致细胞内功能障碍，m6A 介导的 RNA 结合蛋白（RBP）hnRNPA2B1 的识别有利于 EV 加载，而接收细胞中 EV-miRNA 的功能需要它们的 FTO 介导的去甲基化。因此，细胞表达特定的 miRNAs，这些 miRNAs 不会影响内源性转录本，但为细胞间通讯提供调节信息。这突出表明，在将细胞动态与特定 miRNAs 相关联时，应该考虑到更复杂的层面。
