ESC differentiation is the process by which embryonic stem cells (ESCs) develop into specialized cell types. This process is regulated by various signaling pathways and transcription factors that direct the stem cells to adopt specific identities, ultimately contributing to the formation of diverse tissues and organs in the body.

Epigenetic modifications on DNA and histones are closely intertwined, allowing for the dynamic regulation of chromatin structures. This orchestration plays a crucial role in regulating gene expression and influencing cellular functions.

The regulation of gene expression during development and disease is significantly influenced by the marking of DNA, histones, and RNA. Recent findings have established a connection between N6-methyladenosine (m6A), which is added to RNA by the METTL3-METTL14 methyltransferase complex, and histone modifications. However, the relationship between m6A and DNA methylation has been less thoroughly investigated. Giuseppe Quarto’s study reveals that the METTL3-METTL14 complex recruits the DNA methyltransferase DNMT1 to chromatin, facilitating gene-body methylation. They have identified a set of genes whose expression is finely regulated by gene-body 5mC, which enhances transcription, as well as m6A, which leads to transcript destabilization. Their research demonstrates that both METTL3-METTL14-mediated 5mC and m6A are critical for the differentiation of embryonic stem cells into embryoid bodies. Furthermore, the upregulation of essential differentiation genes during early differentiation is dependent on the dynamic interplay between increased 5mC and decreased m6A. These findings offer new insights into the interplay between epigenetics and epitranscriptomics in regulating gene expression and influencing developmental processes and possibly other biological activities.