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When RNA methylation meets DNA methylation: a mechanistic study

par Quarto, Giuseppe
Président du jury Dewachter, Laurence
Promoteur Fuks, François
Publication Non publié, 2025-02-18

Thèse de doctorat

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Résumé :

The intricate interplay between epigenetic modifications on DNA, histones, and RNA is crucial for gene expression regulation. While the connections between RNA methylation, particularly m6A, and histone modifications are gradually emerging, only hints of links between m6A and DNA methylation have been reported. This thesis focuses on the link between m6A RNA methylation, installed by the METTL3-METTL14 complex, and DNA methylation. It aims to explore the potential connection between RNA and DNA methylation, investigating whether direct interactions exist between their respective writer machineries and examining the biological relevance of this connection. The research is structured into two main sections: In the first section, we demonstrate that the METTL3-METTL14 RNA methyltransferase complex directly interacts with DNMT1, a key enzyme for DNA methylation, to recruit it to the chromatin. Through experiments in HeLa cells and mouse embryonic stem cells (mESCs), we reveal that this interaction promotes DNA methylation within gene bodies, independently of m6A modification. Genome-wide analyses further show a tendency for 5mC and RNA m6A to co-occur at shared gene targets. In the second section, we delve into the functional implication of the 5mC-m6A cooccurrence on gene expression and the biological relevance. We demonstrate that the two marks have an opposite role on the same target: gene body 5mC promotes transcription, while m6A reduces transcript stability. During mESC differentiation into embryoid bodies (EBs), this balance shifts. Specifically, as cells exit pluripotency, intragenic 5mC-levels increase while m6A decreases, leading to higher expression of key differentiation genes such as Eomes, Notch2, and Smad3. This study uncovers a novel layer of gene regulation, where m6A and gene body 5mC work in tandem to fine-tune gene expression. Both modifications are essential for stem cell differentiation, with their coordinated dynamics playing a pivotal role in the upregulation of developmental genes. These findings expand our understanding of how epigenetic and epitranscriptomic marks integrate to regulate gene expression in development and potentially other biological processes, providing new insights into the complex mechanisms of gene regulation.