- DNA methyltransferases (DNMTs) are a family of enzymes responsible for catalyzing the transfer of a methyl group to DNA, primarily at the 5-position of cytosine residues within CpG dinucleotides. This epigenetic modification, known as DNA methylation, plays a critical role in regulating gene expression, maintaining genomic stability, and guiding developmental processes in vertebrates and other organisms. By influencing the accessibility of DNA to transcriptional machinery and interacting with methyl-binding proteins and chromatin remodelers, DNMTs serve as key regulators of chromatin structure and gene silencing.
- There are three major functional DNMTs in mammals: DNMT1, DNMT3A, and DNMT3B. DNMT1 is often referred to as the maintenance methyltransferase because it preferentially methylates hemimethylated DNA during DNA replication. It ensures the faithful propagation of existing methylation patterns to daughter strands, thereby preserving epigenetic memory across cell divisions. In contrast, DNMT3A and DNMT3B are known as de novo methyltransferases. They are primarily active during early embryogenesis and cellular differentiation, where they establish new DNA methylation marks on previously unmethylated DNA, thereby laying down cell-type-specific epigenetic landscapes.
- DNA methylation established and maintained by DNMTs contributes to numerous essential biological functions. It is critical for X-chromosome inactivation, genomic imprinting, silencing of repetitive elements, and transcriptional repression of genes. In gene promoters, particularly those rich in CpG islands, methylation often leads to transcriptional silencing by preventing the binding of transcription factors and recruiting methyl-CpG-binding domain (MBD) proteins, which further condense chromatin. Conversely, gene body methylation is sometimes associated with active transcription, suggesting a context-dependent regulatory function.
- Dysregulation of DNMT activity is strongly associated with various diseases, particularly cancer. Overexpression or mutation of DNMTs can result in abnormal methylation patterns, including hypermethylation of tumor suppressor gene promoters and global hypomethylation, which may activate oncogenes or destabilize the genome by reactivating transposable elements. For instance, mutations in DNMT3A are frequently observed in hematological malignancies such as acute myeloid leukemia (AML), contributing to altered differentiation and clonal expansion. Similarly, changes in DNMT expression or function have been linked to developmental disorders and neurological conditions, underscoring the enzyme’s importance beyond oncogenesis.
- Therapeutically, DNMT inhibitors such as azacitidine and decitabine are used in the treatment of certain hematologic cancers. These nucleoside analogs incorporate into DNA and trap DNMTs, leading to passive demethylation during replication. Their use aims to restore the expression of epigenetically silenced tumor suppressor genes and reprogram malignant cells toward a more normal state. However, due to their global effects on DNA methylation, careful dosing and monitoring are necessary to avoid off-target consequences.
