Several lines of evidence point to the involvement of recessive mutations in the predisposition to, and hence initiation of, cancer in vivo. Analyses of the genetic behavior of transformed cells suggest that at least one way to explain these events is to invoke loci which suppress the tumorous phenotype and which are inactivated by mutation. These suppressors are the subject of much speculation, but whether or not they are ultimately determined to be the regulators of differentiation antigens, growth factors, or proto-oncogenes, it is certain that the investigation of such loci will allow yet another glimpse at the inner mysteries of organismal development.

The above experiments support a relatively simple model to explain the role of DNA methylation in vivo. Most tissue-specific genes are methylated. The methyl groups may generate a local chromatin configuration that renders the genes inaccessible, and thus transcriptionally inactive. This would provide a general mechanism for transcriptional repression which may operate independent of the requirement for interactions between cis-acting regulatory elements and tissue-specific factors. In contrast, house-keeping genes may not be affected by this inhibitory mechanism, and are thus available for constitutive expression in all cell types. Activation of tissue-specific genes from their generalized state of repression must first involve recognition of the genes while they are still methylated and this event initiates the process of transcription and concomitant demethylation. In their demethylated state these genes would be stably maintained in an active structure that is generally accessible to the transcriptional machinery of the cell.