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Dissecting de novo methylation

Nature Genetics volume 23, pages 380–382 (1999)Cite this article

The methylation of DNA is fundamental to mammalian development1. This is vividly illustrated by the fact that mouse embryos deficient in Dnmt1, a DNA methyltransferase that methylates cytosine groups, die as a result of genome-wide demethylation2. Dnmt1 seems to be the main enzyme responsible for maintaining methylation after each round of DNA replication. But studies of Dnmt1-deficient embryonic stem cells have revealed that other enzymes must exist to methylate the genome de novo after the wave of global demethylation that occurs during early embryonic development3. Okano et al.4 recently reported that murine Dnmt3a and Dnmt3b are the long-sought mammalian de novo methyltransferases. Their findings, as well as those of Xu et al.5 and Hansen et al.6, also show that mutations of DNMT3B cause a disorder associated with immunodeficiency, centromere instability and facial anomalies (ICF syndrome). This disorder is the only known human condition with constitutive abnormalities in DNA methylation.

An earlier study9 indicated that Dnmt3a has de novo methyltransferase activity; its forced expression in Drosophila melanogaster, which normally lacks methylation, invokes methylation and lethality. The fact that the fly has homologues of methyltransferases and methyl-binding protein indicates that it may have lost methylation recently in its evolutionary lineage but retained downstream mechanisms of methylation-associated gene repression.

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Figure 1: In mammals, methyltransferase enzymes are collectively responsible for introducing (de novo) and maintaining methyl groups covalently attached to cytosine residues.
Figure 2: Mutation of DNMT3B, which causes ICF syndrome, results in loss of methylation from repeat sequences (a) adjacent to centromeres.
Figure 3: Multiradiate chromosome in lymphocyte metaphase spread from individual with ICF syndrome.

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Authors and Affiliations

  1. Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, CB2 4AT, UK

    Wolf Reik & Gavin Kelsey

  2. Max Planck Institute of Molecular Genetics, Berlin, Germany

    Jörn Walter

  3. Jörn Walter

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  1. Wolf Reik
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  2. Gavin Kelsey
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  3. Jörn Walter
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Reik, W., Kelsey, G. & Walter, J. Dissecting de novo methylation. Nat Genet 23, 380–382 (1999). https://doi.org/10.1038/70476

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