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When epigenetics meets epitranscriptomics: a mechanistic study

par Li Greci, Andrea
Président du jury Maenhaut, Carine
Promoteur Fuks, François
Publication Non publié, 2023-11-06

Thèse de doctorat

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Résumé :

Marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. On mRNA, m6A is installed by the METTL3-METTL14 methyltransferase complex. Recent evidence links m6A to histone modifications, but the crosstalk between m6A and DNA methylation remains scarcely explored. Our findings indicate co-occurrence of m6A with gene-body 5mC, this being associated with increased gene expression. Accordingly, METTL3-depleted cells display intragenic DNA hypomethylation and decreased expression of the corresponding genes. Mechanistically, we evidence direct binding of METTL3-METTL14 to DNA methyltransferase DNMT1 and METTL14-mediated recruitment of DNMT1 to chromatin. We show that gene-body 5mC and the mRNA-stability-enhancing effect of coding-sequence m6A both contribute to increased gene expression. We substantiate our findings on embryonic stem cells, where METTL3 regulates gene-body methylation and expression of key differentiation markers. Our results highlight a previously unrecognized layer of gene expression regulation, involving direct mechanistic links between RNA modification and DNA methylation.