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DNA Methyltransferases in Mammalian Development and Genome Defense

Timothy H. Bestor


The mammalian genome is modified by the addition of about 3 × 107 methyl groups, all at the 5 position of cytosine and most at 5′-CpG-3′ dinucleotides. Methylation patterns are transmitted by clonal inheritance (Pfeifer et al. 1990) and increase the information content of the genome (Reinisch et al. 1995); transcription is repressed when CpG sites within promoters are methylated (Iguchi-Ariga and Schaffner 1989). Cytosine methylation is dangerous: 5-methylcytosine (m5C) is the major endogenous mutagen (deamination results in C → T transition mutations at CpG sites, which account for about one-third of all mutations in humans; Bestor and Coxon 1993), and tumor suppressor genes are frequently inactivated by ectopic de novo methylation of promoter regions (Herman et al. 1994). However, there must be benefits that yield a net selective advantage. This is shown by the retention of cytosine methylation by virtually all organisms with genomes of more than 5 × 108 bp (Bestor 1990) and by the fact that perturbations of methylation patterns are lethal to mouse embryos and to differentiated cells (Li et al. 1992). Severe developmental abnormalities are seen when m5C levels are reduced in Arabidopsis as the result of mutations at uncharacterized loci (Vongs et al. 1993) or by expression of a DNA methyltransferase antisense construct (Finnegan, this volume). Although methylation patterns clearly play an essential role in large-genome eukaryotes, the nature of that role is not understood. It is argued here that an understanding of the regulation of de novo methylation will reveal the biological function...

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