Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation

The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m⁶A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m⁶A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m⁶A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m⁶A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m⁶A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.