Figure 2.

Regulation of epigenetic signaling by cofactor competition. Diverse mechanisms of genomic regulation including transcription factor stability, and histone and cytosine methylation status are regulated by α-ketoglutarate-dependent dioxygenases (green arrow). Inactivating mutations in the TCA cycle enzymes FH and SDH or missense mutations in cytosolic IDH1 result in the production of high concentrations of fumarate, succinate, and (R)-2-hydroxyglutarate, which compete with α- ketoglutarate for enzyme active sites (red arrow). Metabolic enzymes are color-coded light blue, with those proteins mutated or overexpressed in cancer outlined in bold red. HIF, hypoxia-inducible factor; SDH, succinate dehydrogenase; FH, fumarate hydratase; IDH, isocitrate dehydrogenase.