Epitranscriptomic N-6-Methyladenosine Modification Is Required for Direct Lineage Reprogramming into Neurons

Abstract

N-6-methyladenosine (m(6)A), a conserved epitranscriptomic modification of eukaryotic mRNA (mRNA), plays a critical role in a variety of biological processes. Here, we report that m(6)A modification plays a key role in governing direct lineage reprogramming into induced neuronal cells (iNs). We found that m(6)A modification is required for the remodeling of specific mRNAs required for the neuronal direct conversion. Inhibition of m(6)A methylation by Mettl3 knockdown decreased the efficiency of direct lineage reprogramming, whereas increased m(6)A methylation by Mettl3 overexpression increased the efficiency of iN generation. Moreover, we found that transcription factor Btg2 is a functional target of m(6)A modification for efficient iN generation. Taken together, our results suggest the importance of establishing epitranscriptomic remodeling for the cell fate conversion into iNs.