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.