CHAPTER 7: Targeting Non-Acetylation Histone Erasers

Histone demethylases have emerged as a new class of non-acetylation histone erasers that control the dynamic and reversible states of histone methylation for gene expression, genome structure, epigenetic signal storage and inheritance. Although identified only recently, increasing lines of evidence suggest that histone demethylases play key roles in various biological processes, including maintenance of pluripotent embryonic stem cells, genome stability, transcription, cell cycle progression and development. The importance of balanced regulation of histone methylation is exemplified by alterations of histone demethylases in a wide array of diseases such as cancers, mental retardation and metabolic disorders. Histone demethylases are classified into the FAD-dependent demethylases, which oxidise the methyl group in mono- and dimethylated histones, and the Jumonji C (JmjC) domain-containing demethylases, which utilise an iron- and α-ketoglutarate-dependent mechanism to hydroxylate and remove the methyl group from mono-, di- and trimethylated histones in a sequence-specific manner. Many demethylases form complexes with other proteins to define their substrate specificity and regulate gene expression in a context-dependent process. Analyses of demethylase structures and catalytic mechanisms have led to the identification, design and development of novel inhibitory chemicals against histone demethylases, which provide the promise for selectively targeting cancers and various other diseases.