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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Acknowledgements
The authors thank all members of the Meissner, Smith and Kretzmer laboratories for thoughtful discussions and feedback in topics related to this manuscript. The authors thank H. Kretzmer, C. Haggerty, J. Charlton, M. Cui, J. Villagrana, R. Tornisiello and K. Tse for discussions on topics related to this work. This work was supported by the Max Planck Society (A.M.), the NIH New Innovator Award DP2HD108774 (Z.D.S.), Mathers Foundation (Z.D.S.) and Chen Innovation Award (Z.D.S.).
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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. A.M and Z.D.S. wrote the article.
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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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Glossary
- ‘2 cell’ or ‘totipotent’ programmes
-
Early zygotic genome activation signatures within mammalian embryos, typically characterized by a limited transcriptional burst from retrotransposon-derived sequences during the early cleavage divisions.
- B compartments
-
Genomic compartments characterized by chromosome capture technologies and found to overlap with numerous additional features of constitutively methylated heterochromatin.
- Bimodal methylation pattern
-
When measured for a population of somatic cells, the CpG methylation status frequently maintains very high methylation (close to 100%) for CpG-poor sequences or very low methylation (close to 0%) for CpG-rich sequences.
- Bivalent domains
-
Genomic territories typically found over developmental gene promoters, with an architecture of broadly distributed histone H3 lysine 27 trimethylation (H3K27me3) and CpG island (CGI)-enriched H3K4me3.
- CXXC domain
-
A cysteine-X-X-cysteine-X-X-cysteine motif-containing zinc finger domain that shows preferential binding to unmethylated CpG-containing sequences and is found within multiple chromatin modifiers associated with CpG island (CGI) regulation.
- DNA methylation valleys
-
(DMVs). Multi-kilobase genomic territories that are generally maintained in a constitutively unmethylated state, often comprise multiple CpG islands (CGIs) and tend to surround the transcription start sites of developmental genes.
- Endogenous retroviruses
-
(ERVs). Endogenous retrotransposons derived from exogenous retroviruses that largely function according to their biology, including tRNA-primed reverse transcription and assembly of cytoplasmic viral-like capsids.
- Epigenetic clocks
-
Inferences of chronological or biological age through the measurement of methylation at limited subsets of CpG dinucleotides.
- Epigenetic transmission
-
The propagation of a phenotypic or molecular signature without underlying genetic control, including over cell division (mitotic) or organismal generations (transgenerational).
- Epi-polymorphisms
-
The within sample-based deviation in CpG methylation patterns across individually measured sequencing reads; generally, higher numbers of epi-polymorphisms are indicative of greater cellular or allelic heterogeneity within the sample.
- Facultative heterochromatin
-
A generic term for more dynamic, less repetitive heterochromatin that emerges within developmental contexts and typically functions in the process of inducible gene regulation.
- Induced pluripotency
-
The direct induction of embryonic stem cell (ESC) transcriptional programmes and functional properties using a reduced number of stem cell-associated factors.
- Intracisternal A-type particles
-
(IAPs). A major rodent endogenous retrovirus (ERV) named for the detection of viral-like particles within the cisternae of the endoplasmic reticulum; a frequent model for characterizing epigenetic regulator function.
- Isocitrate dehydrogenase
-
(IDH). An enzyme that catalyses decarboxylation of isocitrate into α-ketoglutarate, a major metabolic intermediate of the Krebs cycle that also serves as an essential co-factor for histone demethylases and ten–eleven translocation (TET) enzymes.
- Krüppel-associated box domain zinc finger proteins
-
(KRAB-ZFPs). A rapidly evolving gene family that largely functions to repress parasitic genomic elements; these proteins contain an amino-terminal KRAB domain for recruiting epigenetic repressor complexes and a carboxy-terminal array of zinc fingers to enable sequence-specific binding.
- Lamina-associated domains
-
(LADs). Large-scale genomic features characterized by high-frequency interactions with the nuclear lamina, which is enriched for constitutively methylated heterochromatin.
- Large organized chromatin K9 modifications
-
(LOCKs). Large-scale genomic features characterized by generally inert, gene-poor DNA, found via profiling of the heterochromatic modification histone H3 lysine 9 dimethylation (H3K9me2).
- Long interspersed nuclear elements
-
(LINEs). Ancient non-viral derived retrotransposons that comprise large fractions of mammalian genomes and replicate via a unique mechanism that primes reverse transcription directly from host DNA.
- Nucleosome remodelling and deacetylase (NuRD) complex
-
An ATP-dependent chromatin remodelling complex associated with gene silencing and heterochromatin assembly, including subunits involved in nucleosome positioning and histone deacetylation.
- Oncometabolite
-
A term used for metabolites that generically exhibit higher levels in tumours versus healthy cells, including mutant isocitrate dehydrogenase (IDH)-produced 2-hydroxyglutarate that grossly inhibits ten–eleven translocation (TETs) and histone demethylases within glioblastomas (GBMs) and myeloid leukaemias.
- Shannon’s entropy
-
A general measurement of information content within a distribution; used in DNA methylation research to distinguish how intermediate methylation is distributed across cell populations from individually measured sequencing reads.
- Topologically associated domains
-
(TADs). Genomic territories that are predicted by chromatin conformation capture assays to self-interact with a higher than average frequency and are often restricted by CTCF-enriched boundary elements.
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Smith, Z.D., Hetzel, S. & Meissner, A. DNA methylation in mammalian development and disease. Nat Rev Genet 26, 7–30 (2025). https://doi.org/10.1038/s41576-024-00760-8
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DOI: https://doi.org/10.1038/s41576-024-00760-8