Methylation and oxidation in 5′-CpG-3′ and 5′-CpA-3′ dinucleotides. (a) DNA methyltransferases (DNMTs) convert C to 5-methylC (5mC). Tet dioxygenases then convert 5mC to 5-hydroxymethylC (5hmC), 5-formylC (5fC), and 5-carboxyC (5caC) in three consecutive Fe(II)-dependent and α-ketoglutarate-dependent oxidation reactions, without release of formaldehyde (Top). Tet dioxygenases can also convert thymine (5mU) to 5hmU, and potentially to 5fU and 5caU (Bottom). (b) CpG/CpG can be methylated on both strands; while TpG/CpA is intrinsically methylated on one strand (T, 5mU), and the C on the other strand may be methylated as well. (c) 5mC and 5mU (T) contain a methyl group (yellow sphere) in spatially equivalent positions at C5. (d) Dnmt3A and Dnmt3B can methylate cytosine in the context of a CpA/TpG dinucleotide. Tet dioxygenases can oxidize both 5mC and T (5mU).