Epitranscriptomic N⁶-Methyladenosine Modification Is Required for Direct Lineage Reprogramming into Neurons

N⁶-methyladenosine (m⁶A), a conserved epitranscriptomic modification of eukaryotic mRNA (mRNA), plays a critical role in a variety of biological processes. Here, we report that m⁶A modification plays a key role in governing direct lineage reprogramming into induced neuronal cells (iNs). We found that m⁶A modification is required for the remodeling of specific mRNAs required for the neuronal direct conversion. Inhibition of m⁶A methylation by Mettl3 knockdown decreased the efficiency of direct lineage reprogramming, whereas increased m⁶A methylation by Mettl3 overexpression increased the efficiency of iN generation. Moreover, we found that transcription factor Btg2 is a functional target of m⁶A modification for efficient iN generation. Taken together, our results suggest the importance of establishing epitranscriptomic remodeling for the cell fate conversion into iNs.