Establishment of genome methylation patternsDNA methylation in eukaryotes is found only at the 5-position of cytosines (5mC). In vertebrates, 3-8% of cytosines are modified and methylation is found almost exclusively in the short canonical sequence 5'-CpG-3' [45]. Plants generally show a greater fraction of methylated cytosines (4-40%) in part due to the additional methylation of 5'-CpNpG-3' (where N is any base) [44. 125]. Methylcytosine is also S-Adenosylmethionine-Dependent Methyltransferases Downloaded from www.worldscientific.com by NANYANG TECHNOLOGICAL UNIVERSITY on 06/10/16. For personal use only. 342 P. M. Vertino found in some, but not all, fungal species and in these organisms levels range from 0.5-2% of cytosines [3]. A few notable eukaryotic species lack detectable methylation including the yeasts Saccharomyces cerevisiae [3] and Schizosaccharomyces pombe [88], the insect Drosophila melongaster [120], and the nematode Caenorhabditis elegans [99]. However, all long-lived multicellular organisms with genomes of greater than 5xl0 8 bp have methylated genomes and for these, methylation appears necessary for normal development.The distribution of methylation and methylatable sites is non-random in the vertebrate genome. CpG sites have been lost from the vertebrate genome over evolutionary time through the deamination of 5mC to thymidine. A small fraction of the genome in which CpG sites are not under represented are known as CpG 'islands'. CpG islands are frequently found near the 5' ends of genes, and whereas the vast majority of CpG sites in the genome are methylated, most CpG islands are completely devoid of methylation even in the germ line [14]. About half of mammalian genes are thought to have associated CpG islands, particularly housekeeping genes, and the unmethylated state is thought to be permissive for transcription [2,14,36]. Exceptions, where CpG islands are in fact methylated, include genes on the inactive X chromosome, and imprinted genes where dense methylation of CpG islands is part of the mechanism that ensures the heritability of a stably silenced state in somatic cells [90,91]. Clusters of unmethylated CpG residues reminiscent of vertebrate CpG islands are also found in the plant genome, although they are not as frequent as in mammalian genomes and not found at all housekeeping genes.In contrast to prokaryotes in which methylation patterns are a simple function of DNA sequence, methylation patterns in eukaryotes must be cued by more complex signals since methylation of a single locus can differ from cell type to cell type and even between alleles within the same nucleus. In mammals, tissuespecific methylation patterns are re-established at each generation by an ill-defined mechanism that involves the demethylation of gamete-specific methylation in the early zygote followed by a de novo process that methylates most of the genome just prior to implantation of the embryo [52]. How this de novo process selects some sequences for methylation while sparing others (for example, CpG islands) i...