Hypothetical pathways for de novo methylation of gene promoters in cancer precursor cells. (a) Primary silencing by loss of activating transcription factors, followed by secondary de novo methylation. (b) Primary silencing by overexpression of transcriptional repressors, followed by secondary de novo methylation. (c) Primary de novo methylation by hyperexpressed DNA methyltransferase, without loss of transcription factors. (d) Interallelic transfer of DNA methylation at a locus with preexisting allele-specific hypermethylation (either parental imprinting or “first-hit” de novo methylation). Methylated DNA is shown in red. The gene promoter is in blue, and changes in chromatin configuration are indicated by a change in shape. Activating transcription factors are in gray, and repressor proteins are in yellow. The red arrows are methylated repetitive elements, and the black arrows indicate gene transcription. In a–c, DNA methylation is shown as spreading from preexisting methylated sequences within the repetitive elements.