7 Inheritance of Genomic Methylation Patterns

The mammalian genome bears heritable patterns of 5-methylcytosine, most of which is within transposons, tandem repeat sequences, and CpG islands of genes subject to X inactivation. Smaller amounts of methylcytosine are found at single-copy sequences associated with clusters of imprinted genes. Cytosine methylation is required for the transcriptional silencing of transposons, imprinted genes, and some genes on the inactive X chromosome, although the mechanism by which methylation represses transcription is unknown. If methylation in cultured cells is reduced by treatment with inhibitors of DNA cytosine methyltransferases, de novo methylation can restore methylation patterns at repeated sequences but not at single-copy imprinted regions. Ectopic de novo methylation is associated with the heritable inactivation of cellular genes (especially in cultured cells), but the causative role of this methylation is uncertain. In addition, although it is generally believed that there are distinct classes of de novo and maintenance DNA methyltransferases, the biochemical evidence is not fully consistent with this belief. DNA methyltransferase 1 (Dnmt1), which is considered to be the maintenance methyltransferase, has only a modest preference for hemimethylated over unmethylated DNA substrates and is much more abundant and has a higher specific activity on unmethylated DNA than does Dnmt3A or Dnmt3B, which are considered to be obligate de novo DNA methyltransferases. Although the biological importance of DNA methylation in mammals is no longer in doubt, the mechanisms by which sequences are designated for methylation remain poorly understood. It is striking that the DNA methylation systems of vertebrates and flowering plants are so...