Schematic of regulatory components of the epigenome. The epigenome primarily consists of DNA methylation and histone modifications at the nucleosomal level. Most cytosine guanine dinucleotides (CpGs) in the mammalian genome are methylated in the form of 5-methylcytosine (5mC), except for those in CpG islands (CGIs), commonly found near promoter regions. The methylation is catalyzed by DNA methyltransferases (DNMTs). CpG shores, located within 2 kb of CGIs, as well as CpG canyons, which are large conserved regions of hypomethylation, can also be differentially methylated. Active removal of 5mC is catalyzed by the ten-eleven translocation (TET) family of dioxygenases through oxidation of 5mC to 5-hydroxymethylcytosine (5hmC). Isocitrate dehydrogenase 1 (IDH1) and IDH2 catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), a metabolite required for TET catalytic function. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb group (PcG) repressive complex 2 (PRC2), responsible for trimethylation of lysine 27 of histone H3 (H3K27me3), a repressive histone mark that is also regulated by additional sex combs–like 1 (ASXL1). The methylation of H3K4 by mixed-lineage leukemia (MLL), H3K79 by DOT1L, H3R2/R8 by protein arginine methyltransferase 5 (PRMT5), and histone acetylation by histone acetyltransferases (HATs) all promote active transcription. Lysine methylation and acetylation can be removed by demethylases such as lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs). DOT1L, disruptor of telomeric silencing 1–like; me1, monomethylation; me2, dimethylation. Professional illustration by Somersault18:24.