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When the Epigenetic and Epitranscriptomic Worlds Collide: METTL3-METTL14 Recruits DNMT1 to Chromatin

By Stuart P. Atkinson, Ph.D.

November 19, 2025

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The Known Links between the Epigenetic and Epitranscriptomic Worlds

Epigenetics and epitranscriptomics – which include modifications to DNA, RNA, and histone proteins – combine to regulate gene expression under normal and pathogenic conditions. A wide range of recent studies has described the interplay between the N6-methyladenosine (m6A) modification of RNA by the METTL3-METTL14 methyltransferase complex and specific histone modifications; however, links between RNA methylation (m6A) and DNA methylation (5mC) remain somewhat unexplored. For example, the METTL3-METTL14 complex promotes H3K9me2 demethylation and gene expression in a mechanism involving m6A “reader” proteins (Li et al.), and chromatin-associated proteins and histone modifications may guide the recruitment of METTL3-METTL14 to chromatin to promote subsequent m6A deposition (Barbieri et al., Huang et al., and Dou et al.). Furthermore, additional studies have revealed the possibility that METTL3-METTL14 regulate the chromatin landscape independent of m6A (Mu et al. and Dou et al.). Meanwhile, any link between the m6A machinery and DNA methylation has remained less clear and has been described in only a handful of relevant studies (Xu et al., Deng et al., and Sun et al.).

Researchers led by François Fuks (Université libre de Bruxelles) sought to fill this knowledge gap and now, a recent Cell study reveals that METTL3-METTL14 can recruit the DNA methyltransferase DNMT1 (the key maintenance methyltransferase in mammals) to chromatin to support the DNA methylation of gene-body regions; furthermore, they describe a new mechanism that integrates the transcriptional impact of RNA methylation and DNA methylation to regulate the expression of genes essential to the differentiation of embryonic stem cells (Quarto, Li Greci, and Bizet et al.). Incredible things happen when the worlds of epigenetics and epitranscriptomics collide!

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Linking DNA Methylation and the RNA Methylation Machinery Builds Bridges Between Worlds

In the initial stages of this bridge-building new study, the authors identified the recruitment of the DNA methylation (5mC) writer DNMT1 by METTL3-METTL14 as the driving mechanism behind gene-body DNA methylation. Specifically, they discovered that the chromatin-bound METTL3-METTL14 complex interacted with DNMT1 via an essential arginine/glycine-rich RNA-binding domain of METTL14 (Thandapani et al.) to favor gene-body 5mC deposition. Of note, this mechanism remains distinct from the better appreciated H3K36me3-DNMT3A-DNMT3B axis (Weinberg et al., Baubec et al., and Neri et al.), while studies have highlighted the methylation of 60-80% of CpG sites in mammals and greater methylation levels at intragenic regions compared to intergenic regions (Lister et al. and Meissner et al.).

Based on this interaction, the authors next identified a distinct mode of gene expression regulation arising from the frequent co-occurrence of 5mC and m6A at gene loci, which combines the transcriptional effect of gene body 5mC with the post-transcriptional effect of m6A on the transcript. While gene body DNA methylation correlates with active transcription (Maunakea et al.), the deposition of m6A on RNA prompts a transcript-destabilizing effect that helps to maintain gene expression dynamics (Geula et al. and Wu et al.). The authors note that the combination of these opposing regulatory mechanisms has parallels with bivalent domains of histone modifications with opposing transcriptional influence (H3K4me3 and H3K27me3) that coordinate gene expression regulation in stem cells and during development (Macrae et al.).

Finally, the team revealed the significance of this newly described gene expression regulation mode in the differentiation of embryonic stem cells into embryoid bodies. They discovered that a shift in the balance of 5mC, favoring gene transcription, and m6A, reducing transcript stability, significantly influenced the expression of genes critical for the differentiation process. Said genes include Eomes (multiple lineage specification), Smad3 (mesoderm and endoderm specification), and Notch2 (tissue and organ patterning).

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The METTL3-METTL14-DNMT1 Axis: A Critical Regulator of Stem Cell Differentiation

Overall, this fascinating collision between the worlds of epigenetics and epitranscriptomics has revealed a novel gene regulatory mechanism – the METTL3-METTL14-DNMT1 axis - that impinges on the differentiation of embryonic stem cells but likely contributes to a wealth of additional biological processes. The authors hope that their findings will pave the way for future breakthroughs in both normal and pathological developmental biology; however, they acknowledge specific limitations that must be addressed first. Exploring whether METTL3-METTL14 facilitates DNMT1 recruitment to promoters, enhancers, and repetitive elements remains a fascinating concept, while single-cell analyses of the METTL3-METTL14-DNMT1 axis in differentiating stem cells may help to define nuanced differences between individual cell types.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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