Waalwijk and Flavell (1978) were first to use the isoschizomeric restriction endonuclease pair Hpall and MspI to test for the presence of 5mC in individual gene sequence. Both enzymes recognize the same site CCGG, but Hpall does not cleave the sequence methylated at the internal C, whereas MspI is not affected by such methylation. In most somatic tissues, including erythroid and nonerythroid tissues, a CCGG site present in the major intron of the rabbit в-globin gene seemed to be ~50% methylated. The same site seemed to be 100% methylated in sperm DNA and ~80% methylated in brain DNA. It was the first direct indication on reverse correlation between DNA methylation and gene activity. The next confirmation came from the Walter Doerfler’s laboratory, where an inverse correlation between the extent of methylation and transcription of integrated adenovirus 12 genes in transformed hamster cells was noted (Sutter & Doerfler, 1980). We found that the patterns of DNA methylation in the rat liver change significantly upon induction of gene expression with hydrocortisone (Romanov & Vanyushin, 1981; Vanyushin, Nemirovsky, et al., 1973). These initial studies elicited an avalanche of similar investigations on a large number of eukaryotic genes. Now, it is widely believed that specific promoter methylation plays a crucial role in the stable silencing of eukaryotic genes, although the function of DNA methylation seems to vary with genomic sequence context, and the relationship between DNA methylation and transcription is more nuanced than it was realized at first (Jones, 2012). The connection between promoter methylation and inhibition of its activity is not obligatory. In most cases DNA methylation of promoter region does interfere with transcription by inhibiting binding of respective protein factors. However, there are some examples of positive effects of promoter methylation on transcription (Gustems et al., 2014). DNA methylation can either inhibit or stimulate binding of transcription regulatory proteins, and the effects of the binding could be either activation or repression of gene activity, dependent on protein function.