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Rethinking how DNA methylation patterns are maintained

Abstract

DNA methylation patterns are set up early in mammalian development and are then copied during the division of somatic cells. A long-established model for the maintenance of these patterns explains some, but not all, of the data that are now available. We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA.

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Figure 1: Current model for the establishment and inheritance of DNA methylation patterns.
Figure 2: Revised model for the maintenance of DNA methylation patterns.

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Acknowledgements

This work was supported by the US National Institutes of Health grants R37 CA082422 (P.A.J.), 5R01 CA083867 (P.A.J.) and 5R01 CA124518 (G.L.).

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Glossary

Chromatin remodelling factor

A protein that has the capacity to remodel chromatin, often using the energy of ATP, so that gene transcription can be activated or silenced.

CpG island

A DNA sequence of at least 500 bp with a GC content greater than 55% and a higher CpG dinucleotide content than is average for the genome (that is, an observed/expected ratio of >0.65). These regions are typically undermethylated and are found upstream of many mammalian genes.

ICF syndrome

(Immunodeficiency, centromere instability and facial anomalies syndrome). A rare autosomal recessive disorder that is linked to mutations in the DNA methyltransferase 3B (DNMT3B) gene.

Imprinting

The differential expression of genes depending on whether they were inherited maternally or paternally.

Nucleosome

The basic unit of chromatin. A nucleosome contains approximately 146 bp of DNA wrapped around a histone octamer.

Polycomb complex

A complex of repressive chromatin proteins that maintain states of gene expression throughout development.

X chromosome inactivation

The process that occurs in female mammals by which gene expression from one of the pair of X chromosomes is downregulated to match the levels of gene expression from the single X chromosome that is present in males. The inactivation process involves a range of epigenetic mechanisms on the inactivated chromosome, including changes in DNA methylation and histone modifications.

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Jones, P., Liang, G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10, 805–811 (2009). https://doi.org/10.1038/nrg2651

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