Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Histone methylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity. Enzymes that directly remove methyl marks from histones have recently been identified, revealing a new level of plasticity within this epigenetic modification system. Here we analyse the evolutionary relationship between Jumonji C (JmjC)-domain-containing proteins and discuss their cellular functions in relation to their potential enzymatic activities.
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Acknowledgements
R.J.K. is funded by the Canadian Institutes of Health Research. Work in the Zhang laboratory is funded by grants from the US National Institutes of Health and the Howard Hughes Medical Institute.
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Glossary
- Cupin
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A domain found within a superfamily of proteins that are characterized by their β-barrel tertiary structure (in Latin, cupa means small barrel). Proteins containing this domain include metal coordinating oxygenases and other proteins that lack enzymatic activity.
- Oxoferryl
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High-valent oxoiron (IV) intermediates that act as the oxidizing species in JmjC-catalysed demethylase reactions.
- Bayesian inference of phylogeny
-
A statistical method based on a quantity called the posterior probability distribution, which is the probability of a phylogenetic tree conditioned on the observations (multiple sequence alignments). Phylogeny is calculated by determining the probability that the model (tree) is correct given the observed data (clustal alignment).
- Tudor domains
-
A repeated domain first identified in the Drosophila melanogaster Tudor protein, which has subsequently been identified in other proteins as a domain capable of mediating protein–nucleotide and protein–protein interactions. Recently, some Tudor domains have been shown to specifically associate with methylated lysine residues.
- NCoR corepressor complex
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An HDAC-containing protein complex that has general roles in the transcriptional repression of hormone-regulated genes through interaction with unliganded nuclear hormone receptors.
- Tetratricopeptide repeat
-
A structural motif responsible for mediating protein–protein interactions. The tetracopeptide repeat motif consists of tandem repeats of 34 amino-acid residues.
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Klose, R., Kallin, E. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7, 715–727 (2006). https://doi.org/10.1038/nrg1945
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DOI: https://doi.org/10.1038/nrg1945
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