Cell: Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation (Gupta Lab)

Giuseppe Quarto1,12 ∙ Andrea Li Greci1,12 ∙ Martin Bizet1,12 ∙ Audrey Penning1 ∙ Irina Primac1 ∙ Frédéric Murisier1 ∙ Liliana Garcia-Martinez2 ∙ Rodrigo L. Borges2 ∙ Qingzeng Gao3,4 ∙ Pradeep K.R. Cingaram2 ∙ Emilie Calonne1 ∙ Bouchra Hassabi1 ∙ Céline Hubert1 ∙ Adèle Herpoel1 ∙ Pascale Putmans1 ∙ Frédérique Mies1 ∙ Jérôme Martin1 ∙ Louis Van der Linden1 ∙ Gaurav Dube1 ∙ Pankaj Kumar1 ∙ Romuald Soin5 ∙ Abhay Kumar6 ∙ Anurag Misra6 ∙ Jie Lan1 ∙ Morgane Paque7,8 ∙ Yogesh K. Gupta6 ∙ Arnaud Blomme7,8 ∙ Pierre Close7,8 ∙ Pierre-Olivier Estève9 ∙ Elizabeth A. Caine10 ∙ Kristin M. Riching10 ∙ Cyril Gueydan5 ∙ Danette L. Daniels11 ∙ Sriharsa Pradhan9 ∙ Ramin Shiekhattar2 ∙ Yael David3,4 ∙ Lluis Morey2 ∙ Jana Jeschke1 ∙ Rachel Deplus1 ∙ Evelyne Collignon1 ∙ François Fuks1,13

Summary

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.

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