Hypermethylation

Hypermethylation refers to an increase in DNA methylation at specific genomic regions, most commonly at cytosine residues within CpG dinucleotides. In humans, DNA methylation is mediated by DNA methyltransferases, including maintenance DNMT1 and de novo DNMT3A and DNMT3B. Hypermethylation denotes an abnormal elevation of methylation relative to normal tissue and can occur in promoters, gene bodies, or repetitive elements.

Promoter region hypermethylation is commonly associated with transcriptional silencing of nearby genes. Mechanistically, methyl-CpG-binding domain proteins recruit co-repressors and histone deacetylases, leading to condensed chromatin and reduced transcription.

Consequences and examples: in development and imprinting, methylation patterns are essential; abnormal hypermethylation can cause diseases, notably cancer, where tumor suppressor genes are often silenced by promoter hypermethylation (for example, p16INK4A, MLH1, MGMT). Colorectal cancers may exhibit CIMP, a phenotype characterized by widespread promoter hypermethylation. MGMT promoter methylation, in particular, correlates with better response to alkylating agents in glioblastoma.

Detection and clinical use: methylation status is assessed by methods such as bisulfite sequencing, methylation-specific PCR, and array-based approaches. Hypermethylation status serves as a biomarker for prognosis and therapy selection in several cancers.

Therapeutic implications: DNA methyltransferase inhibitors, including azacitidine and decitabine, can reduce methylation and reactivate silenced genes, and are used in myelodysplastic syndromes and some leukemias; research continues on their use in solid tumors.