demethylates

Demethylates refers to processes or enzymes that remove methyl groups from substrates in biology. The most studied contexts are demethylation of DNA cytosine residues and histone tails, which together regulate gene expression through epigenetic mechanisms. In common usage, demethylates can describe enzymatic activity that reverses methylation, distinct from methylation events themselves.

DNA demethylation occurs through passive and active pathways. Passive demethylation happens when DNA is replicated without the maintenance methyltransferase DNMT1, leading to dilution of methylation marks. Active demethylation involves the TET family enzymes (TET1, TET2, TET3), which oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine. These oxidized forms are then removed by base excision repair, often via thymine DNA glycosylase (TDG), culminating in unmethylated cytosine. This process is important in development, cellular reprogramming, and dynamic gene regulation.

Histone demethylation targets methyl groups on histone tails, affecting chromatin structure and transcription. Two major families of histone demethylases exist: the LSD1/KDM1 family, which uses a flavin adenine dinucleotide (FAD) cofactor, and the JmjC domain-containing demethylases (KDM2–KDM7), which require Fe(II) and α-ketoglutarate. These enzymes can remove mono-, di-, or tri-methyl marks depending on the specific enzyme, influencing activation or repression of gene expression in context-specific complexes.

Understanding demethylases is central to epigenetic regulation in development, differentiation, and disease, including cancer, and ongoing research seeks to map their substrates and therapeutic potential.