The orchestrated interplay between DNA methylation and N6-methyladenosine modification: <i>status quo</i> and future perspectives

DNA methylation (DNAme) and N6-methyladenosine (m6A) represent key mechanisms in epigenetic and epitranscriptomic regulation, respectively. While DNAme is a well-established modification, m6A has more recently emerged as a central focus of epitranscriptomic research. This review comprehensively explores the dynamic crosstalk between DNAme and m6A, addressing the molecular intricacies and functional consequences of their interplay. A systematic literature search conducted in Web of Science Core Collection identified 972 publications related to both modifications. After rigorous screening, 29 studies directly investigating interactions between DNAme and m6A were included for in-depth analysis. These interactions were systematically classified into six distinct modes: (1) DNAme-mediated regulation of m6A; (2) m6A-dependent modulation of DNAme; (3) indirect interplay mediated by intermediate factors; (4) direct bilateral regulation between DNAme and m6A; (5) cooperative targeting of common downstream genes or biological processes; and (6) co-expression patterns suggestive of functional interplay. This categorization provides a novel conceptual framework that integrates disparate mechanistic insights, highlights under-explored areas, and proposes new hypotheses for future research. By synthesizing and structuring current knowledge, this review serves as a foundational resource for understanding the complex relationship between these two modifications and facilitates the identification of novel regulatory axes in epigenomic and epitranscriptomic research.