Study of 5mC-DNA, m6A-RNA and RNA-expression in HeLa, ES and EB [ActinoD in HeLa]

Marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links 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 stems cells to 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 new dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development, most likely among other biological processes.