2. Academic Validation
  3. m6A modification inhibits miRNAs' intracellular function, favoring their extracellular export for intercellular communication

m6A modification inhibits miRNAs' intracellular function, favoring their extracellular export for intercellular communication

  • Cell Rep. 2024 Jun 25;43(6):114369. doi: 10.1016/j.celrep.2024.114369.
Sabrina Garbo 1,  Daniel D'Andrea 2,  Alessio Colantoni 3,  Francesco Fiorentino 4,  Antonello Mai 5,  Andres Ramos 6,  Gian Gaetano Tartaglia 7,  Andrea Tancredi 8,  Marco Tripodi 9,  Cecilia Battistelli 10
Affiliations

Affiliations

  • 1 Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
  • 2 School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
  • 3 Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy.
  • 4 Center for Life Nano- and Neuro-Science, RNA Systems Biology Lab, Fondazione Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy.
  • 5 Department of Drug Chemistry and Technologies Sapienza University of Rome, Ple. Aldo Moro 5, 00185 Rome, Italy.
  • 6 Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6XA, UK.
  • 7 Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy.
  • 8 Dipartimento Metodi e Modelli per l'Economia, il Territorio e la Finanza MEMOTEF, Sapienza University of Rome, 00185 Rome, Italy.
  • 9 Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. Electronic address: marco.tripodi@uniroma1.it.
  • 10 Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. Electronic address: cecilia.battistelli@uniroma1.it.
PMID: 38878288 DOI: 10.1016/j.celrep.2024.114369
Abstract

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.

Keywords

A2B1; AGO2; CP: Molecular biology; EVs; FTO; METTL3; epitranscriptomics; intercellular communication; m6A; miRNAs.

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