The diverse roles of DNA methylation in mammalian development and disease


DNA methylation is of paramount importance for mammalian embryonic development. DNA methylation has numerous functions: it is implicated in the repression of transposons and genes, but is also associated with actively transcribed gene bodies and, in some cases, with gene activation per se. In recent years, sensitive technologies have been developed that allow the interrogation of DNA methylation patterns from a small number of cells. The use of these technologies has greatly improved our knowledge of DNA methylation dynamics and heterogeneity in embryos and in specific tissues. Combined with genetic analyses, it is increasingly apparent that regulation of DNA methylation erasure and (re-)establishment varies considerably between different developmental stages. In this Review, we discuss the mechanisms and functions of DNA methylation and demethylation in both mice and humans at CpG-rich promoters, gene bodies and transposable elements. We highlight the dynamic erasure and re-establishment of DNA methylation in embryonic, germline and somatic cell development. Finally, we provide insights into DNA methylation gained from studying genetic diseases.

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Fig. 1: DNA methylation machinery and mechanisms.
Fig. 2: Targeting DNA methylation to CGI promoters.
Fig. 3: DNA methylation-based regulation of transposons.
Fig. 4: DNA methylation reprogramming in development.


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The laboratory of D.B. is part of the Laboratoire d’Excellence (LABEX) entitled DEEP (11-LBX0044) and is supported by the European Research Council (ERC) (grant ERC-Cog EpiRepro).

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The authors contributed equally to all aspects of the article.

Correspondence to Deborah Bourc’his.

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Supplementary information


Pericentromeric satellite repeats

Tandem repeats enriched in heterochromatin modifications such as DNA methylation and histone H3 Lys9 trimethylation.


Transposable elements that propagate in the genome through RNA intermediates and reverse transcription.

Whole-genome bisulfite sequencing

Sodium bisulfite treatment converts unmodified cytosines — but not (hydroxy)methylated cytosines — into uracils (thymines following PCR). Paired with next-generation sequencing, this technique generates genome-wide, single-nucleotide resolution maps of DNA methylation.

Intergenerational epigenetic inheritance

Epigenetic information that is inherited from the parents (for example, genomic imprinting).

Transgenerational epigenetic inheritance

Epigenetic information that is inherited from generations that were not exposed to the initial cue that caused the epigenetic change.

Inner cell mass

Refers to the pluripotent cells in the blastocyst of preimplantation embryos, which can be derived and cultured as embryonic stem cells.

Neomorphic mutations

Typically, dominant mutations, which confer altered expression or novel function for the protein product.

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Greenberg, M.V.C., Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol 20, 590–607 (2019).

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