JmjC-domain-containing proteins and histone demethylation

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Abstract
Modification of histone molecules within chromatin has a profound effect on genome structure and function. More specifically, methylation of histone lysine residues is involved in regulating transcription, epigenetic inheritance and controlling cell fate. The recent identification of histone demethylase enzymes has demonstrated that histone methylation is a dynamic and reversible process, in contrast to the long-held opinion that this was a static modification. The Jumonji C (JmjC) domain can demethylate histones by an oxidative mechanism requiring Fe(II) and alpha-ketoglutarate (αKG) as cofactors, in addition to carrying out protein hydroxylation reactions. Phylogenetic categorization based on JmjC-domain homology and protein domain architecture shows seven distinct JmjC-protein groupings. So far, three of these groupings encompass site-specific histone demethylases, with the enzymatic activity of the remaining groups remaining unknown. Many of the uncharacterized JmjC-protein family members contain residues within the enzyme cofactor-binding sites which are compatible with enzymatic activity, indicating that additional JmjC proteins will probably have roles in histone demethylation and chromatin metabolism. Several JmjC-domain-containing proteins have been functionally implicated in inherited disease and cancer, indicating that these enzymes have important roles in cellular homeostasis and might be suitable targets for therapeutic intervention.