m6A modification inhibits miRNAs’ intracellular function, favoring their extracellular export for intercellular communication
Sabrina Garbo,
Daniel D’Andrea,
Alessio Colantoni,
Francesco Fiorentino,
Antonello Mai,
Andres Ramos,
Gian Gaetano Tartaglia,
Andrea Tancredi,
Marco Tripodi,
Cecilia Battistelli
Affiliations
Sabrina Garbo
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
Daniel D’Andrea
School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK
Alessio Colantoni
Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy
Francesco Fiorentino
Center for Life Nano- and Neuro-Science, RNA Systems Biology Lab, Fondazione Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy
Antonello Mai
Department of Drug Chemistry and Technologies Sapienza University of Rome, Ple. Aldo Moro 5, 00185 Rome, Italy
Andres Ramos
Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6XA, UK
Gian Gaetano Tartaglia
Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152 Genova, Italy
Andrea Tancredi
Dipartimento Metodi e Modelli per l’Economia, il Territorio e la Finanza MEMOTEF, Sapienza University of Rome, 00185 Rome, Italy
Marco Tripodi
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; Corresponding author
Cecilia Battistelli
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; Corresponding author
Summary: 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.
