METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation

Luca Pandolfini, Isaia Barbieri, Andrew J. Bannister, Alan Hendrick, Byron Andrews, Natalie Webster, Pierre Murat, Pia Mach, Rossella Brandi, Samuel C. Robson, Valentina Migliori, Andrej Alendar, Mara d’Onofrio, Shankar Balasubramanian, Tony Kouzarides
Year of publication
Journal name
Molecular Cell
E-pub date
Friday, April 19, 2019

7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.

Research Programme
Paediatric Cancer