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Functions of DNA methylation: islands, start sites, gene bodies and beyond

Nature Reviews Genetics volume 13, pages 484492 (2012) | Download Citation


DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

Key points

  • DNA methylation is an epigenetic mark that can be mitotically inherited and is involved in adding stability to the repression of transcription when it is located at the start sites of mammalian genes. Our ability to obtain complete methylomes has transformed our appreciation of the role of DNA methylation in epigenetic processes.

  • DNA methylation in the bodies of genes has long been ignored but might be involved in differential promoter usage and also in transcription elongation and alternative splicing. Repetitive DNA from intragenomic parasites is heavily methylated, which allows transcription of the host gene at the same time as preventing transcription initiation of the repetitive DNA.

  • Methylation of control regions outside of the transcription start sites — such as enhancers and insulators — is increasingly being recognized as being functionally important.

  • Demethylation of DNA is now accepted as being essential for embryonic development and seems to occur mainly in regions of DNA that are not CpG islands; thus, methylation patterns are increasingly being realized as being far more dynamic than previously recognized.

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Funding for this work was provided by the US National Institutes of Health grants 5 R37 CA 082422–082413 and 5 R01 CA 083867–083812. The author thanks C. Andreu-Vieyra and J.-S. You for help with the figures.

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  1. USC Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, California 90089–99176, USA.

    • Peter A. Jones


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The author declares no competing financial interests.

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Correspondence to Peter A. Jones.


CpG islands

CpG-rich regions of DNA that are often associated with the transcription start sites of genes and that are also found in gene bodies and intergenic regions.

Bisulphite-treated DNA

Bisulphite treatment of DNA converts cytosine to uracil but leaves 5-methylcytosine intact. Thus, 5-methylcytosine patterns can be mapped by subsequent sequencing.


DNA elements that control interactions between enhancers and promoters.

Ten-eleven translocation

(TET). Proteins of this type were recently shown to catalyse the conversion of 5-methylcytosine to 5-hydroxymethylcytosine.

Activation-induced cytidine deaminase

(AID). An enzyme that removes the amino group from cytosine or 5-methylcytosine. It is involved in class switch recombination and DNA demethylation.

Thymine DNA glycosylase

A protein that is involved in the repair of T:G mismatches that are often caused by 5-methylcytosine deamination and that participates in DNA demethylation.

Nucleosome-depleted regions

(NDRs). Regions of DNA that are not extensively wrapped up in nucleosomes. They can be seen at transcription start sites and other regulatory regions such as enhancers.

Polycomb proteins

Polycomb proteins participate in the silencing of genes by mechanisms that do not involve DNA methylation. They often silence genes that are key regulators of differentiation.

Imprinted genes

Imprinted genes show parent-of-origin expression and are controlled by epigenetic processes, including DNA methylation.

X-chromosome inactivation

One of the two X chromosomes in female mammalian somatic cells is stably silenced by epigenetic processes, including DNA methylation, to achieve dosage compensation.

Fragile X syndrome

A developmental disorder triggered by the genetic expansion of triplet repeats near the promoter of the FMR gene, which leads to its silencing, DNA methylation and to the disease phenotype.

Immunodeficiency, centromere instability and facial anomalies syndrome

(ICF syndrome). This can be caused by mutations in DNA methyltransferase 3B (DNMT3B) and leads to centromeric instability, developmental abnormalities and immune deficiencies.

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