A ROLE FOR DNA METHYLATION IN VERTEBRATE GENE-EXPRESSION

Methyl-5-cytosine (m5C) represents 0.75–2.4 mol% of all vertebrate DNA bases and is localized within transcriptionally inactive DNA (1, 2). This review addresses the distribution and formation of m5C in vertebrate DNA in regard to its functional role in the control of gene expression. Early studies established that transcriptionally inactive mouse satellite DNA contains two to four times more m5C than bulk DNA and is enriched in methylated CpT, TpC, and CpC dinucleotides. The distribution of m5C within gene coding sequences different than the generalized, heavy methylation of satellite DNA. Methyl-5-cytosine is concentrated in the CpG dinucleotides of transcriptionally inactive genes. Transcriptionally active genes are depleted in m5C and are associated with methylation-free CpG islands, DNA sequences 500–2000 base pairs in length with an overall G - C content of 50–70% and a near random frequency of CpG dinucleotides. CpG islands are now known to occur in housekeeping genes that are expressed in all cell types and in genes whose expression is limited to specialized cell types (3). Methylation-free CpG islands frequently predict the 5′-end of transcriptionally active DNA sequences. Thus in many instances, tissue-specific heterogeneity in the methylation status of CpG islands can account for the association between m5C and tissue-specific gene repression established by the traditional method of digestion of genomic DNA with methylation-sensitive restriction endonucleases, followed by Southern hybridization analyses with genespecific probes. © 1990 by The Endocrine Society.