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DNA methylation landscapes: provocative insights from epigenomics

Key Points

  • DNA methylation is an epigenetic mark that is associated with gene silencing.

  • Novel high-throughput techniques have begun to generate much larger scale maps of DNA methylation than were previously available.

  • The new information has broadly confirmed several conclusions that were based on analysis of specific regions of the genome. For example, many promoters in mammalian genome are marked by unmethylated CpG islands.

  • This new data shows, however, that CpG islands are often found at intergenic regions and can acquire methylation in somatic cells. Evidence for tissue-specific CpG methylation patterns revives the idea that gene expression might be controlled by altered methylation of regulatory elements.

  • An unexpected finding is that the bodies of active genes in plants and animals are often heavily methylated. The function of gene-body methylation is presently unknown, but might serve to suppress intragenic transcription initiation.

  • Emerging high-throughput DNA sequencing technologies promise to provide complete DNA methylation maps that will transform our understanding of this epigenetic mark.

Abstract

The genomes of many animals, plants and fungi are tagged by methylation of DNA cytosine. To understand the biological significance of this epigenetic mark it is essential to know where in the genome it is located. New techniques are making it easier to map DNA methylation patterns on a large scale and the results have already provided surprises. In particular, the conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged. Not only is promoter methylation often highly dynamic during development, but many organisms also seem to target DNA methylation specifically to the bodies of active genes.

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Figure 1: DNA methylation landscapes in fungi, animals and plants.
Figure 2: Gene-body methylation on the human active X chromosome.
Figure 3: Evolution of eukaryotic DNA methylation patterns.

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Acknowledgements

This work was supported by a grant from the Wellcome Trust. We thank A. Deaton for constructive criticism.

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Correspondence to Miho M. Suzuki.

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Glossary

Imprinted gene

A gene that is expressed or silenced depending on which parent contributed it to the zygote. In a mouse cell, for example, the paternal insulin-like growth factor allele is expressed, but the maternal allele is not. In some cases, imprinting depends on differential DNA methylation of gene regulatory regions.

CpG island

(CGI). A DNA patch of approximately 1,000 bp, within which the dinucleotide CpG occurs at close to its expected frequency. This contrasts with the majority of the vertebrate genome, in which CpG is depleted. Despite the abundance of CpGs that could potentially be methylated, CGIs are unmethylated in germ cells and most are also DNA methylation free in somatic cells. In mammals, CGIs are GC-rich in base composition (65%) compared with the genome as a whole (40%).

454 sequencing and Solexa bisulphite sequencing

Independent proprietary high-throughput DNA-sequencing technologies that both use massively parallel sequencing-by-synthesis approaches. These new methods allow an increase in generated sequence per run of about two orders of magnitude compared with conventional Sanger sequencing technologies, and therefore allow rapid comprehensive sequence screening of large genomic fractions or whole genomes.

Heterochromatic knob

A chromosomal region that can be identified microscopically as being darkly stained compared with surrounding chromatin. DNA sequence analysis has shown that knobs often contain highly repeated DNA sequences. They were described initially in the 1930's by McClintock during her studies of maize chromosome structure.

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Suzuki, M., Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9, 465–476 (2008). https://doi.org/10.1038/nrg2341

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