Methylation

Methylation is the enzymatic transfer of a methyl group (−CH3) to a substrate, most commonly to DNA, RNA, or proteins. It is typically driven by methyltransferases that use S-adenosylmethionine (SAM) as the methyl donor. Methylation can alter chemical properties, interactions, and function, and its patterns are tightly regulated in development and cellular signaling. Across organisms, methylation modulates gene expression, chromatin structure, and metabolic pathways.

DNA methylation in many eukaryotes centers on cytosine in CpG dinucleotides. DNA methyltransferases, including DNMT1 (maintenance) and DNMT3A/3B (de novo), establish and propagate methylation patterns. Methylation in gene promoters is commonly associated with transcriptional repression, while methylation within gene bodies can correlate with active or repressed states depending on context. Dynamic regulation by TET enzymes enables active demethylation, linking DNA methylation to development, imprinting, and environmental responses.

Protein and histone methylation modulates chromatin and protein function. Histone methyltransferases add methyl groups to lysine or arginine residues on histones, producing marks such as H3K4me3 (often activating) and H3K9me3 or H3K27me3 (repressive). Histone demethylases remove these marks, allowing plasticity in gene expression. Protein methylation also affects non-histone targets, influencing enzymatic activity, interactions, and localization, and thereby participating in signaling pathways and protein turnover.

RNA methylation, particularly N6-methyladenosine (m6A), is a widespread post-transcriptional modification that regulates RNA stability, splicing, export, and translation. Writers (e.g., METTL3/METTL14), erasers (e.g., FTO, ALKBH5), and readers (e.g., YTH proteins) coordinate its dynamic deposition and interpretation. Methylation processes are linked to one-carbon metabolism, relying on the folate and methionine cycles to supply SAM; disruptions are associated with development, aging, cancer, and neurological disorders.