SINCE ITS FIRST recognition in 1948, the fifth base of human DNA, 5-methylcytosine (5-mC) has generated much interest and considerable controversy during attempts to understand its significance (for review, see Weissbach1). DNA methylation in eukaryotes involves addition of a methyl group to the carbon 5 position of the cytosine ring (Fig 1). This reaction is catalyzed by DNA methyltransferase in the context of the sequence 5-CG-3, which is also referred to as a CpG dinucleotide. It is the most common eukaryotic DNA modification and is one of the many epigenetic (alteration in gene expression without a change in nucleotide sequence) phenomena. Although extensive in plants and mammals, the absence of detectable DNA methylation in some eukaryotes such as Drosophila2 and Saccharomyces cerevisiae3 has raised doubts about its significance in normal development and tissue-specific gene expression. However, recent studies showing abnormal development and embryonic lethality in transgenic mice expressing decreased but not completely absent DNA Methyltransferase (MTase) activity after DNA-MTase gene knockout4 lends support to a critical role for DNA methylation in developmental gene regulation. Others have proposed that the control of intragenomic parasites is the primary function of DNA methylation in mammalian cells. 5

In this review, we will discuss the fundamental aspects of DNA methylation and its role in transcription repression, neoplasia, and transgene silencing and during development. In the interest of brevity, the role of DNA methylation in genomic imprinting and X chromosome inactivation are not discussed here, but have been reviewed recently elsewhere. 6-8