Lysine Demethylation in Pathogenesis

Epigenetics has major impact on normal development and pathogenesis. Regulation of histone methylation on lysine and arginine residues is a major epigenetic mechanism and affects various processes including transcription and DNA repair. Histone lysine methylation is reversible and is added by histone lysine methyltransferases and removed by histone lysine demethylases. As these enzymes are also capable of writing or erasing lysine modifications on non-histone substrates, they were renamed to lysine demethylases (KDMs) in 2007. Since the discovery of the first lysine demethylase LSD1/KDM1A in 2004, eight more subfamilies of lysine demethylases have been identified and further characterized. The joint efforts by academia and industry have led to the development of potent and specific small molecule inhibitors of KDMs for treatment of cancer and several other diseases. Some of these inhibitors have already entered clinical trials since 2013, less than 10 years after the discovery of the first KDM. In this chapter, we briefly summarize the major roles of histone demethylases in normal development and human diseases and the efforts to target these enzymes to treat various diseases.