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

DNA methylation; DNMT1; ESCs; METTL14; METTL3; differentiation; epigenetics; epitranscriptomics; gene expression; m(6)A; Methyltransferases; Mettl3 protein, mouse; Adenosine; N-methyladenosine; DNA (Cytosine-5-)-Methyltransferase 1; Mettl14 protein, mouse; Dnmt1 protein, mouse; Chromatin; Animals; Mice; DNA Methylation; Embryonic Stem Cells/metabolism; Epigenesis, Genetic; Embryoid Bodies/metabolism; Embryoid Bodies/cytology; Chromatin/metabolism; Humans; Mouse Embryonic Stem Cells/metabolism; Gene Expression Regulation; Methyltransferases/metabolism; Methyltransferases/genetics; Cell Differentiation; Adenosine/analogs & derivatives; Adenosine/metabolism; DNA (Cytosine-5-)-Methyltransferase 1/metabolism; DNA (Cytosine-5-)-Methyltransferase 1/genetics; m6A; Embryoid Bodies; Embryonic Stem Cells; Mouse Embryonic Stem Cells; Biochemistry, Genetics and Molecular Biology (all)

Abstract :

[en] 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.

Research Center/Unit :

Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium.

Disciplines :

Genetics & genetic processes

Author, co-author :

Quarto, Giuseppe; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Li Greci, Andrea; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Bizet, Martin; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Penning, Audrey; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Primac, Irina; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Murisier, Frédéric; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium

Garcia-Martinez, Liliana; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

Borges, Rodrigo L; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

Gao, Qingzeng; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA

Cingaram, Pradeep K R; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

More authors (31 more)

Language :

English

Title :

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

Publication date :

20 February 2025

Journal title :

Cell

ISSN :

0092-8674

eISSN :

1097-4172

Publisher :

Elsevier, United States

Volume :

188

Issue :

Pages :

998 - 1018

Peer reviewed :

Peer Reviewed verified by ORBi

Funding text :

HEK2935XUAS cells, mouse ESC J1 WT/Mettl3 KO, WT/Dnmt1 KO, and E14TG2a WT/Mettl14 KO were kindly provided by the laboratories of Pr. Bastian Stielow (Germany), Pr. Howard Y. Chang (USA), Pr. Fabio Spada (Germany), and Pr. Laixin Xia (China), respectively. G.Q., A.L.G., M.B., A.P., I.P., F. Murisier, B.H., J.M., L.V.d.L., P.K., G.D., J.J., and E. Collignon were supported by the Belgian FRS-FNRS, FRIA, or T\u00E9l\u00E9vie. Q.G. and A.L.G. were supported by the Fondation Rose et Jean Hoguet and the Fondation Jaumotte-Demoulin and Fonds David and Alice Van Buuren. F.F. is a ULB professor. R.D. is a ULB lecturer. This work was partially supported by R01GM141349 and R01GM146409 from the National Institute of General Medical Sciences to L.M. We thank the Sylvester Comprehensive Cancer Center Onco-Genomics Core Facility for high-throughput sequencing. This work was supported by funding from the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, and grants R01GM078455 from the National Institute of Health to R.S. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA240139. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was partially supported by the Welch Foundation (AQ-2101-20220331) and the National Institute of Allergy and Infectious Diseases (R01AI161363) to Y.K.G. F.F.\u2019s lab was funded by grants from the FNRS and T\u00E9l\u00E9vie, the \u201CAction de Recherche Concert\u00E9e\u201D (ARC) (AUWB-2018-2023 ULB-No 7), a Walloon Region grant (Win2Wal), FNRS Welbio grants (FNRS-WELBIO-CR-2017A-04 and FNRS-WELBIO-CR-2019A-04R), the FWO and FNRS under the Excellence of Science (EOS O.0020.22/RG3483) programme, the ULB Foundation, the Belgian Foundation against Cancer (FCC 2016-086 FAF-F/2016/872), and H2020-MSCA-ITN ROPES.

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since 16 April 2025

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