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Cited by 50Epigenetics and DNA MethylationRNA modifications and cancerGenomics and Chromatin Dynamics

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

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Quarto, Giuseppe, Li Greci, Andrea, Bizet, Martin, Penning, Audrey, Primac, Irina, Murisier, Frédéric, Garcia-Martinez, Liliana, Borges, Rodrigo L. +33 more·2025·Cell
DOI 10.1016/j.cell.2024.12.009PMC PMC12160003
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Abstract

The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m 6 A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m 6 A 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 m 6 A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m 6 A 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 m 6 A. 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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  • A recent report demonstrated crosstalk between m6A RNA methylation and 5mC DNA methylation by METTL14-mediated recruitment of DNMT1 to chromatin, and the balance between these two marks controls key differentiation genes in mESCs.

    “A recent report demonstrated crosstalk between m6A RNA methylation and 5mC DNA methylation by METTL14-mediated recruitment of DNMT1 to chromatin, and the balance between these two marks controls key differentiation genes in mESCs (Quarto et al., 2025).”

    From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Quarto et al., 2025

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Cited by

Sorted by citations

Authors
Quarto, G., Li Greci, A., Bizet, M., Penning, A., Primac, I., Murisier, F., Garcia-Martinez, L., Borges, R. L., Gao, Q., Cingaram, P. K. R., Calonne, E., Hassabi, B., Hubert, C., Herpoel, A., Putmans, P., Mies, F., Martin, J., Van der Linden, L., Dube, G., Kumar, P., Soin, R., Kumar, A., Misra, A., Lan, J., Paque, M., Gupta, Y. K., Blomme, A., Close, P., Estève, P.-O., Caine, E. A., Riching, K. M., Gueydan, C., Daniels, D. L., Pradhan, S., Shiekhattar, R., David, Y., Morey, L., Jeschke, J., Deplus, R., Collignon, E., & Fuks, F.
Affiliations
  • Université Libre de Bruxelles (BE)
  • University of Miami (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Liège (BE)
  • New England Biolabs (United States) (US)
  • Promega (United States) (US)
  • Foghorn Therapeutics (United States) (US)
Corresponding author
Fuks, François
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2025-02
Volume
188
Issue
4
Pages
998-1018.e26
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2024.12.009
PMC
PMC12160003
OpenAlex
W4406509358
Cited by
50
References
12
Citations by year
2026: 28 · 2025: 22
FWCI
13.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • ORBi (University of Liège) (submittedVersion, other-oa)
Funders
  • Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
  • National Institute of Allergy and Infectious Diseases (R01AI161363)
  • Fondation Rose et Jean Hoguet
  • National Institutes of Health (P30CA240139)
  • National Institute of General Medical Sciences
  • Waalse Gewest
  • Fonds Wetenschappelijk Onderzoek
  • Welch Foundation
  • FNRS (FNRS-WELBIO-CR-2017A-04, FNRS-WELBIO-CR-2019A-04R)
  • National Cancer Institute
  • Australian Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
N6-methyladenosine, DNMT1, DNA methylation, embryonic stem cell differentiation, embryoid bodies, epitranscriptomics, epigenetics, transcript stability, chromatin recruitment, gene expression regulation
MeSH terms
Mouse Embryonic Stem Cells, DNA (Cytosine-5-)-Methyltransferase 1, Adenosine, Animals, Cell Differentiation, Chromatin, Humans, Methyltransferases, DNA Methylation, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Embryoid Bodies

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