Exploring the brain epitranscriptome: perspectives from the NSAS summit

Summary RNA modifications play critical roles in important biological processes. However, the functions of N 6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

N 6 -methyladenosine (m 6 A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m 6 A regulates mammalian brain development is unknown. Here we show that m 6 A depletion by Mettl14 knockout in embryonic mouse brains prolongs cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m 6 A depletion by Mettl3 knockdown also leads to prolonged cell cycle and maintenance of radial glia cells. m 6 A-sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, cell cycle and neuronal differentiation, and m 6 A-tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional pre-patterning in cortical neural stem cells. m 6 A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m 6 A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m 6 A-tagging of transcripts related to brain disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis. m6A-dependent mRNA decay is critical for transcriptional pre-patterning in mammalian cortical neurogenesis.