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. 2025 Feb 20;188(4):998-1018.e26.
doi: 10.1016/j.cell.2024.12.009. Epub 2025 Jan 17.

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

Giuseppe Quarto  1 , Andrea Li Greci  1 , Martin Bizet  1 , Audrey Penning  1 , Irina Primac  1 , Frédéric Murisier  1 , Liliana Garcia-Martinez  2 , Rodrigo L Borges  2 , Qingzeng Gao  3 , Pradeep K R Cingaram  2 , Emilie Calonne  1 , Bouchra Hassabi  1 , Céline Hubert  1 , Adèle Herpoel  1 , Pascale Putmans  1 , Frédérique Mies  1 , Jérôme Martin  1 , Louis Van der Linden  1 , Gaurav Dube  1 , Pankaj Kumar  1 , Romuald Soin  4 , Abhay Kumar  5 , Anurag Misra  5 , Jie Lan  1 , Morgane Paque  6 , Yogesh K Gupta  5 , Arnaud Blomme  6 , Pierre Close  6 , Pierre-Olivier Estève  7 , Elizabeth A Caine  8 , Kristin M Riching  8 , Cyril Gueydan  4 , Danette L Daniels  9 , Sriharsa Pradhan  7 , Ramin Shiekhattar  2 , Yael David  3 , Lluis Morey  2 , Jana Jeschke  1 , Rachel Deplus  1 , Evelyne Collignon  1 , François Fuks  10
Affiliations

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

Giuseppe Quarto et al. Cell. .

Abstract

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.

Keywords: DNA methylation; DNMT1; ESCs; METTL14; METTL3; differentiation; epigenetics; epitranscriptomics; gene expression; m(6)A.

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Conflict of interest statement

Declaration of interests F.F. is a co-founder of Epics Therapeutics (Gosselies, Belgium).

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