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Review
. 2025 Jan;26(1):7-30.
doi: 10.1038/s41576-024-00760-8. Epub 2024 Aug 12.

DNA methylation in mammalian development and disease

Zachary D Smith  1 , Sara Hetzel  2 , Alexander Meissner  3
Affiliations
Review

DNA methylation in mammalian development and disease

Zachary D Smith et al. Nat Rev Genet. 2025 Jan.

Abstract

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.

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Conflict of interest statement

Competing interests: A.M. and Z.D.S. are inventors on a patent related to hypermethylated CGI targets in cancer. Z.D.S. and A.M. are co-founders and scientific advisers of Harbinger Health. S.H. declares no competing interests.

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