DNA Methyltransferases in Mammalian Development and Genome Defense

Abstract

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...