1 Nature Reviews Genetics 2006 Vol: 7(9):715-727. DOI: 10.1038/nrg1945

JmjC-domain-containing proteins and histone demethylation

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.

Mentions
Figures
Figure 1: Chemical mechanism by which three distinct classes of enzymes antagonize histone methylation.a | PADI4 (petidylarginine deiminase 4) is a Ca2+ dependent deiminase that antagonizes arginine methylation by demethylimination. Demethylimination of mono-methyl arginine is shown, with the methyl group shown in red. b | LSD1 (lysine specific demethylase 1) is proposed to mediate demethylation of mono and dimethylated lysine residues through an amine oxidation reaction that uses flavin (FAD) as a cofactor. Loss of the methyl group from monomethyl lysine occurs through an imine intermediate (1), which is hydrolysed to form formaldehyde by a non-enzymatic process (2). c | JHDM histone demethylases can demethylate mono-, di- and trimethylated lysine by an oxidative mechanism that requires Fe(II) and KG as cofactors. Demethylation is thought to occur by direct hydroxylation of the methyl group (1), which results in an unstable hydroxymethyl product that is spontaneously released as formaldehyde (2). Figure 2: The JmjC domain contains residues required for Fe(II) and KG binding.a | A three-dimensional cartoon depicting the polypeptide backbone structure of the JmjC (Jumonji C) domain of JHMD3A/JMJD2A. The eight -sheets of the cofactor-coordinating pocket are shown in grey, with the Fe(II) ion in red and KG in blue. The -helical region that associates with the zinc ion is shown in green and the zinc molecule in purple. b | A schematic representation of the JmjC domain showing the position of the Fe(II)-binding (top) and KG-binding (bottom) residues. The amino-acid identity of residues within active hydroxylases and demethylases and amino-acid substitutions found in other JmjC-domain proteins are shown above and below the indicated cofactor-binding residue position. Figure 3: Phylogenetic relationship of JmjC-domain-containing proteins from model organisms.The phylogenetic relationship between the JmjC (Jumonji C)-domain-containing proteins from model organisms (Examples from Schizosaccharomyces pombe (sp); Caenorhabditis elegans (ce); Saccharomyces cerevisiae (sc); Drosophila melanogaster (dm); Homo sapiens (hs); Mus musculus (mm)) was determined by multiple sequence alignment and Bayesian inference analysis (Box 1). For phylogenetic analysis, all posterior probabilities of clade partitions that were <100% are shown; the values represent the percentage of sampled trees used in the analysis that contained the consensus partition (left). By combining information from the phylogenetic analysis (left) and the domain architecture of the full-length protein (right), seven evolutionarily conserved groups of JmjC-domain-containing proteins were defined. The asterisk indicates proteins that were placed in a given group based on homology within the JmjC domain, but that lack some aspects of the domain architecture found in their related orthologues. In the JARID group, we have created two subgroups to emphasize the high level of homology between the JARID1 and JARID2 proteins, despite divergence in the spatial arrangement of the conserved domains. The JmjC-domain-only group has been divided into eight subgroups based on similarity within the JmjC domain, as determined by phylogenetic analysis alone. JmjN, Jumonji N domain; PHD, plant homeobox domain; TPR, tetracopeptide repeat domain; ZF-like, zinc-finger-like domain. Figure 4: JHDM1 proteins are H3K36 demethylases.a | The domain architecture of JHDM1 proteins is highly conserved in flies, mice and humans, but orthologues found in lower eukaryotes lack several of the domains found in higher eukaryotes. (JmjC, Jumonji C domain; PHD, plant homeobox domain; LRR, leucine rich repeats) b | Multiple sequence alignment of the JHDM1 group JmjC domains shows a high degree of homology within the predicted Fe(II)-binding (red) and KG-binding sites (blue), suggesting that most JHDM1 orthologues are likely to be H3K36 demethylases. A substitution mutation within the third Fe(II)-binding residue of the Schizosaccharomyces pombe (sp) orthologue, Epe1, abrogates its H3K36 demethylase activity. Examples from Homo sapiens (hs), Mus musculus (mm), Drosophila melanogaster (dm), Caenorhabditis elegans (ce) and Saccharomyces cerevisiae (sc). Figure 5: PHF2/PHF8 proteins are related to the JHDM1 histone demethylases.a | PHF2/PHF8 orthologues are found in worms, mice and humans but absent from flies. Each member of this group has a JmjC (Jumonji C) domain and a closely associated PHD (plant homeobox) domain. b | With the exception of mouse and human PHF2, the PHF2/PHF8 group of proteins are conserved within the predicted Fe(II)-binding (red) and KG-binding (blue) residues of the JmjC domain. The close similarity of the PHF2/PHF8 JmjC domain with that of JHDM1 proteins suggests that these proteins are excellent histone demethylase candidates. Examples from Homo sapiens (hs), Mus musculus (mm) and Caenorhabditis elegans (ce). Figure 6: The JARID1/2 group contains potentially active enzymes.a | The domain architecture of proteins within the JARID1/2 group is conserved; the JARID1 and JARID2 subgroups subdivision is based on spatial arrangement of these domains. (JmjC, Jumonji C domain; JmjN, Jumonji N domain; PHD, plant homeobox domain). b | Multiple sequence alignment demonstrates that the majority of the JARID1 proteins contain conserved residues within the Fe(II)-binding site (red) and KG-binding site (blue), which are compatible with enzymatic activity. By contrast, the residues important for cofactor binding are substituted in the JARID2 subgroup and in some Schizosaccharomyces pombe (sp) proteins of the JARID1 subgroup (JmjC domains with substituted residues are denoted with an asterisk). Examples from Homo sapiens (hs), Drosophila melanogaster (dm), Caenorhabditis elegans (ce) and Saccharomyces cerevisiae (sc). Figure 7: The JHDM3/JMJD2 proteins are H3K9/K36 demethylases.a | JHDM3/JMJD2 orthologues are found from yeast to human and all group members contain a JmjC (Jumonji C) and JmjN (Jumonji N) domain. Members of this group contain additional C-terminal domains, which are probably involved in protein targeting (PHD, plant homeobox domain). b | With the exception of the budding yeast protein Gis1, all JHDM3/JMJD2 group members have conserved residues within the Fe(II)-binding site (red) and KG-binding site (blue), indicating that uncharacterized members of this group could be functional histone demethylases. Examples from Homo sapiens (hs), Mus musculus (mm), Drosophila melanogaster (dm), Caenorhabditis elegans (ce) and Saccharomyces cerevisiae (sc). Figure 8: UTX/UTY proteins are poorly characterized proteins with conserved JmjC domains.a | UTX/UTY orthologues are found from worms to humans and are characterized by a JmjC (Jumonji C) domain and TPR (tetratricopeptide) repeats. b | High levels of conservation are evident within the Fe(II)-binding site (red) and KG-binding site (blue) of UTX/UTY proteins, indicating that these are potentially active enzymes. Yellow shading indicates the amino-acid insertion within the UTX/UTY JmjC domain. Examples from Homo sapiens (hs), Mus musculus (mm), Drosophila melanogaster (dm) and Caenorhabditis elegans (ce). Figure 9: JHDM2 proteins are H3K9 demethylases.a | JHDM2 proteins are found from flies to humans and have a zinc-finger (ZF)-like domain in addition to a JmjC (Jumonji C) domain. b | With the exception of the human and mouse Hairless (HR) proteins, the Fe(II)-binding site (red) and KG-binding site (blue) are conserved amongst JHDM2 orthologues, indicating that these proteins are probably functional H3K9 demethylases. Yellow shading indicates the amino-acid insertion within the JHDM2 JmjC domain. Examples from Homo sapiens (hs), Mus musculus (mm) and Drosophila melanogaster (dm).
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References
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    • . . . Most histone lysine methylation is mediated by a large family of methyltransferase enzymes that contain an enzymatic SET domain1.However, it was only in 2000 that the widespread importance of the SET domain was discovered92 . . .
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    • . . . PADI4 (Petidylarginine deiminase 4) was the first to be identified; it functions as a histone deiminase that converts methyl-arginine to citrulline as opposed to directly reversing arginine methylation7, 8 . . .
    • . . . With the identification of enzymes that antagonize histone methylation7, 8, 9, 13, we are on the cusp of another rapid advancement in our understanding . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  8. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545-553.References 7 and 8 identify PADI4 as the first enzyme capable of antagonizing histone arginine methylation , (2004) .
    • . . . PADI4 (Petidylarginine deiminase 4) was the first to be identified; it functions as a histone deiminase that converts methyl-arginine to citrulline as opposed to directly reversing arginine methylation7, 8 . . .
    • . . . With the identification of enzymes that antagonize histone methylation7, 8, 9, 13, we are on the cusp of another rapid advancement in our understanding . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  9. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953.Identifies the first true histone demethylase enzyme, LSD1, which utilizes flavin as a cofactor to carry out an oxidative demethylation reaction , (2004) .
    • . . . LSD1 (Lysine specific demethylase 1) was the founding member of a second class of enzymes that directly reverse histone H3K4 or H3K9 modifications by an oxidative demethylation reaction in which flavin is a cofactor9, 10 . . .
    • . . . With the identification of enzymes that antagonize histone methylation7, 8, 9, 13, we are on the cusp of another rapid advancement in our understanding . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  10. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436-439 , (2005) .
    • . . . LSD1 (Lysine specific demethylase 1) was the founding member of a second class of enzymes that directly reverse histone H3K4 or H3K9 modifications by an oxidative demethylation reaction in which flavin is a cofactor9, 10 . . .
  11. Lee, M. G., Wynder, C., Cooch, N. & Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432-435 , (2005) .
    • . . . Full enzymatic activity of LSD1 requires its association with other proteins, such as the CoREST (restin corepressor) complex, indicating that regulatory subunits can have a role in modulating demethylase activity11, 12 . . .
  12. Shi, Y. J. et al. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 857-864 , (2005) .
    • . . . Full enzymatic activity of LSD1 requires its association with other proteins, such as the CoREST (restin corepressor) complex, indicating that regulatory subunits can have a role in modulating demethylase activity11, 12 . . .
  13. Tsukada, Y. et al. Histone demethylation by a family of JmjC-domain-containing proteins. Nature 439, 811-816.The authors used a novel in vitro histone demethylase assay to biochemically purify and characterize the first JmjC-domain-containing histone demethylase enzyme , (2006) .
    • . . . The third and largest class of demethylase enzymes contain a Jumonji C (JmjC) domain and catalyse lysine demethylation of histones through an oxidative reaction that requires iron Fe(II) and -ketoglutarate (KG) as cofactors13 . . .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . Given that a related group of oxygenases, the AlkB family of proteins, were previously shown to remove methylation from amine groups in modified DNA, it was predicted that chromatin-associated JmjC-domain-containing proteins might be involved in demethylation of modified arginine or lysine amine groups within histones13, 24 . . .
    • . . . This was confirmed by an unbiased activity-based biochemical purification, which identified a JmjC-domain-containing protein, JHDM1, as a H3K36-specific demethylase13 . . .
    • . . . Using a novel activity-based histone demethylase assay, we recently identified the JHDM1 family of histone demethylases, and showed that the JmjC domain can specifically mediate Fe(II) and KG-dependent histone demethylation13 . . .
    • . . . Both human JHDM1 homologues (JHDM1A and JHDM1B) and their orthologue from budding yeast are H3K36 histone demethylases13 . . .
    • . . . Mutation of these residues directly affects enzymatic activity both in vitro and in vivo13 . . .
    • . . . This is exemplified in the fission yeast JHDM1 orthologue, Epe1, which has a naturally occurring histidine-to-tyrosine substitution in the third Fe(II)-binding residue that renders the enzyme inactive towards histone substrates13 . . .
    • . . . With the identification of enzymes that antagonize histone methylation7, 8, 9, 13, we are on the cusp of another rapid advancement in our understanding . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  14. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483-495.The authors biochemically purified a novel JmjC-domain-containing histone H3K9 demethylase and demonstrated its role in androgen receptor-mediated gene activation , (2006) .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . Consistent with this notion, JHDM2A associates with the androgen receptor and is important for H3K9 demethylation during ligand-dependent activation of androgen-responsive genes14 . . .
    • . . . Using the same activity-based assay that successfully identified JHDM1, we have recently demonstrated that the JHDM2A is a mono- and dimethyl H3K9-specific demethylase14 . . .
    • . . . In response to hormone treatment, JHDM2A associates with the androgen receptor (AR) and contributes to AR-mediated gene activation, probably by keeping the promoter free of H3K9 methylation14 . . .
  15. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467-481 , (2006) .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . Several groups have recently shown that the mammalian JHDM3/JMJD2 proteins are functional histone demethylases that target H3K9 and H3K36, and require both the JmjN and JmjC domains for activity15, 16, 17, 18 . . .
    • . . . RNAi-mediated knockdown of the C. elegans JHDM3/JMJD2 orthologue perturbed H3K9 and H3K36 methylation levels, which resulted in CEP-1/p53-dependent germ-cell apoptosis and caused defects in the progression of meiotic double-strand break repair15 . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  16. Klose, R. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and 36. Nature 442, 312-316 , (2006) .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . The JHDM3 and JMJD2 H3K9 and H3K36 demethylases regulate gene expression16, antagonize HP1 recruitment to chromatin16, 17, 18 and are required for the proliferative capacity of specific cancer cell lines17 . . .
    • . . . Several groups have recently shown that the mammalian JHDM3/JMJD2 proteins are functional histone demethylases that target H3K9 and H3K36, and require both the JmjN and JmjC domains for activity15, 16, 17, 18 . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  17. Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307-311 , (2006) .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . The JHDM3 and JMJD2 H3K9 and H3K36 demethylases regulate gene expression16, antagonize HP1 recruitment to chromatin16, 17, 18 and are required for the proliferative capacity of specific cancer cell lines17 . . .
    • . . . Several groups have recently shown that the mammalian JHDM3/JMJD2 proteins are functional histone demethylases that target H3K9 and H3K36, and require both the JmjN and JmjC domains for activity15, 16, 17, 18 . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  18. Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557-1562.References 15 to 18 demonstrate that the JHDM3/JMJD2 histone demethylase enzymes are capable of removing the trimethyl modification state , (2006) .
    • . . . So far, JHDMs have been shown to reverse H3K36 (JHDM1) (Ref. 13), H3K9 (JHDM2A) (Ref. 14) and both H3K9 and H3K36 (JHDM3 and JMJD2A–D) methylation15, 16, 17, 18 . . .
    • . . . Several groups have recently shown that the mammalian JHDM3/JMJD2 proteins are functional histone demethylases that target H3K9 and H3K36, and require both the JmjN and JmjC domains for activity15, 16, 17, 18 . . .
    • . . . So far, histone demethylases have been shown to counteract histone modifications that oppose the transcription state of a given gene, and to remove histone modifications during the transition from one transcriptional state to another7, 8, 9, 13, 15, 16, 17, 18 . . .
  19. Clissold, P. M. & Ponting, C. P. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2. Trends Biochem. Sci. 26, 7-9.The authors identify bioinformatic and structural similarities between metalloenzymes and JmjC-domain-containing proteins , (2001) .
    • . . . The JmjC domain was first defined based on the amino-acid similarities in the Jarid2 (Jumonji), Jarid1C (Smcx), and Jarid1A (RBP2) proteins19, 20, 21 . . .
    • . . . Homology between the JmjC and cupin metalloenzyme domains19, 22 led to the identification of the JmjC-domain-containing factor inhibiting hypoxia (FIH) as an active protein oxygenase that can hydroxylate asparagine residues23 . . .
  20. Takeuchi, T. et al. Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. Genes Dev. 9, 1211-1222.The authors cloned the Jumonji protein in a gene-trap screen for factors involved in neural tube formation. The JmjC domain was later named on the basis of its presence in the Jumonji protein , (1995) .
    • . . . The JmjC domain was first defined based on the amino-acid similarities in the Jarid2 (Jumonji), Jarid1C (Smcx), and Jarid1A (RBP2) proteins19, 20, 21 . . .
    • . . . Mouse Jarid2 was first identified in a gene-trap screen as an important factor in neural tube formation, and was named Jumonji (in reference to the Japanese character) because of the abnormal cruciform shape that the neural groove formed in the homozygous null mouse20, 56 . . .
  21. Balciunas, D. & Ronne, H. Evidence of domain swapping within the Jumonji family of transcription factors. Trends Biochem. Sci. 25, 274-276 , (2000) .
    • . . . The JmjC domain was first defined based on the amino-acid similarities in the Jarid2 (Jumonji), Jarid1C (Smcx), and Jarid1A (RBP2) proteins19, 20, 21 . . .
  22. Dunwell, J. M. & Gane, P. J. Microbial relatives of seed storage proteins: conservation of motifs in a functionally diverse superfamily of enzymes. J. Mol. Evol. 46, 147-154 , (1998) .
    • . . . Homology between the JmjC and cupin metalloenzyme domains19, 22 led to the identification of the JmjC-domain-containing factor inhibiting hypoxia (FIH) as an active protein oxygenase that can hydroxylate asparagine residues23 . . .
  23. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466-1471.The authors identify the JmjC-domain-containing protein FIH as an asparaginyl hydroxylase enzyme and for the first time demonstrate enzymatic activity for a mammalian JmjC-domain protein , (2002) .
    • . . . Homology between the JmjC and cupin metalloenzyme domains19, 22 led to the identification of the JmjC-domain-containing factor inhibiting hypoxia (FIH) as an active protein oxygenase that can hydroxylate asparagine residues23 . . .
    • . . . It functions as an asparagine protein hydroxylase for the hypoxia inducible factor (HIF) transcription factor23 . . .
    • . . . Under normal oxygen conditions, HIF is hydroxylated by FIH in the cytoplasm on a single asparagine, which can inhibit binding of the p300/CBP histone acetyltransferase23, 25, 78 . . .
  24. Trewick, S. C., McLaughlin, P. J. & Allshire, R. C. Methylation: lost in hydroxylation? EMBO Rep. 6, 315-320.The authors propose that JmjC-domain-containing proteins might function as histone demethylases based on the function of the fission yeast JmjC-domain protein Epe1 in regulating silent chromatin structure , (2005) .
    • . . . Given that a related group of oxygenases, the AlkB family of proteins, were previously shown to remove methylation from amine groups in modified DNA, it was predicted that chromatin-associated JmjC-domain-containing proteins might be involved in demethylation of modified arginine or lysine amine groups within histones13, 24 . . .
    • . . . The structure of FIH in complex with Fe(II) and KG has proved to be a useful template for assigning predicted cofactor-binding sites and secondary structure to other JmjC-domain-containing proteins24, 25, 26, 27 (Supplementary information S2 (figure)) . . .
  25. Dann, C. E., Bruick, R. K. & Deisenhofer, J. Structure of factor-inhibiting hypoxia-inducible factor 1: an asparaginyl hydroxylase involved in the hypoxic response pathway. Proc. Natl Acad. Sci. USA 99, 15351-15356 , (2002) .
    • . . . Based on the crystal structure of FIH and the recently solved structure of the catalytic domains of JHDM3A/JMJD2A, the JmjC domain has been shown to fold into eight -sheets, thereby forming an enzymatically active pocket that coordinates Fe(II) and KG25, 26, 27, 28 (Fig. 2a) . . .
    • . . . Under normal oxygen conditions, HIF is hydroxylated by FIH in the cytoplasm on a single asparagine, which can inhibit binding of the p300/CBP histone acetyltransferase23, 25, 78 . . .
    • . . . The structure of FIH in complex with Fe(II) and KG has proved to be a useful template for assigning predicted cofactor-binding sites and secondary structure to other JmjC-domain-containing proteins24, 25, 26, 27 (Supplementary information S2 (figure)) . . .
  26. Elkins, J. M. et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF1. J. Biol. Chem. 278, 1802-1806 , (2003) .
    • . . . Based on the crystal structure of FIH and the recently solved structure of the catalytic domains of JHDM3A/JMJD2A, the JmjC domain has been shown to fold into eight -sheets, thereby forming an enzymatically active pocket that coordinates Fe(II) and KG25, 26, 27, 28 (Fig. 2a) . . .
    • . . . The structure of FIH in complex with Fe(II) and KG has proved to be a useful template for assigning predicted cofactor-binding sites and secondary structure to other JmjC-domain-containing proteins24, 25, 26, 27 (Supplementary information S2 (figure)) . . .
  27. Lee, C., Kim, S. J., Jeong, D. G., Lee, S. M. & Ryu, S. E. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau. J. Biol. Chem. 278, 7558-7563 , (2003) .
    • . . . Based on the crystal structure of FIH and the recently solved structure of the catalytic domains of JHDM3A/JMJD2A, the JmjC domain has been shown to fold into eight -sheets, thereby forming an enzymatically active pocket that coordinates Fe(II) and KG25, 26, 27, 28 (Fig. 2a) . . .
    • . . . The structure of FIH in complex with Fe(II) and KG has proved to be a useful template for assigning predicted cofactor-binding sites and secondary structure to other JmjC-domain-containing proteins24, 25, 26, 27 (Supplementary information S2 (figure)) . . .
  28. Chen, Z. et al. Structural insights into histone demethylation by JMJD2 family members. Cell 125, 691-702.A report of the first crystal structure of the enzymatic domain of an active JmjC-domain-containing histone demethylase, JHDM3A/JMJD2A , (2006) .
    • . . . Based on the crystal structure of FIH and the recently solved structure of the catalytic domains of JHDM3A/JMJD2A, the JmjC domain has been shown to fold into eight -sheets, thereby forming an enzymatically active pocket that coordinates Fe(II) and KG25, 26, 27, 28 (Fig. 2a) . . .
    • . . . The crystal structure of the N-terminal region of JHDM3A/JMJD2A (which contains the JmjN and JmjC domains) in association with Fe(II) and KG provided the first detailed view of the core catalytic domain of an active histone demethylase (Fig. 2a)28 . . .
  29. Clifton, I. J. et al. Structural studies on 2-oxoglutarate oxygenases and related double-stranded -helix fold proteins. J. Inorg. Biochem. 100, 644-669 , (2006) .
    • . . . To catalyse histone demethylation, the cofactor-bound JmjC domain is thought to produce a highly reactive oxoferryl species that hydroxylates the methylated substrate, allowing spontaneous loss of the methyl group as formaldehyde29 (Fig. 1) . . .
  30. Chenna, R. et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res. 31, 3497-3500 , (2003) .
    • . . . A combination of multiple sequence alignment30 and Bayesian inference phylogeny31, 32was used to visualize the evolutionary relationship between the JmjC domains of the proteins within our database (Fig. 3) . . .
  31. Huelsenbeck, J. P. & Ronquist, F. MrBayes: Bayesian inference of phylogenetic trees. Bioinformatics 17, 754-755 , (2001) .
    • . . . A combination of multiple sequence alignment30 and Bayesian inference phylogeny31, 32was used to visualize the evolutionary relationship between the JmjC domains of the proteins within our database (Fig. 3) . . .
  32. Ronquist, F. & Huelsenbeck, J. P. MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19, 1572-1574 , (2003) .
    • . . . A combination of multiple sequence alignment30 and Bayesian inference phylogeny31, 32was used to visualize the evolutionary relationship between the JmjC domains of the proteins within our database (Fig. 3) . . .
  33. Pothof, J. et al. Identification of genes that protect the Caenorhabditis elegans genome against mutations by genome-wide RNAi. Genes Dev. 17, 443-448 , (2003) .
    • . . . Little is known about the biological function of JHDM1 proteins, although the C. elegans orthologue can suppress spontaneous mutations33 and the fission yeast orthologue functions to limit heterochromatic domains at the mating type locus34. . . .
  34. Ayoub, N. et al. A novel JmjC domain protein modulates heterochromatization in fission yeast. Mol. Cell. Biol. 23, 4356-4370.The authors show that Epe1 has important roles in modulating heterochromatin formation and provide a basis for speculation that the JmjC domain might have histone demethylase activity , (2003) .
    • . . . Little is known about the biological function of JHDM1 proteins, although the C. elegans orthologue can suppress spontaneous mutations33 and the fission yeast orthologue functions to limit heterochromatic domains at the mating type locus34. . . .
  35. Bai, C. et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86, 263-274 , (1996) .
    • . . . F-box proteins are known to associate with S-phase kinase-associated protein 1A (SKP1) to form the SKP1–cullin–F-box protein E3 ubiquitin ligase complex35, which suggests that JHDM1 might link histone demethylation to protein ubiquitylation . . .
  36. Ayton, P. M., Chen, E. H. & Cleary, M. L. Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol. Cell. Biol. 24, 10470-10478 , (2004) .
    • . . . This raises the possibility that the targeting of JHDM1-mediated histone demethylation is linked to DNA methylation status36, 37, 38. . . .
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    • . . . This raises the possibility that the targeting of JHDM1-mediated histone demethylation is linked to DNA methylation status36, 37, 38. . . .
  38. Lee, J. H. & Skalnik, D. G. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian SET1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast SET1/COMPASS complex. J. Biol. Chem. 280, 41725-41731 , (2005) .
    • . . . This raises the possibility that the targeting of JHDM1-mediated histone demethylation is linked to DNA methylation status36, 37, 38. . . .
  39. Zofall, M. & Grewal, S. I. Swi6/HP1 recruits a JmjC-domain protein to facilitate transcription of heterochromatic repeats. Mol. Cell 22, 681-692.The authors demonstrate that Epe1 functions in heterochromatin to promote Pol II accessibility by counteracting repressive chromatin , (2006) .
    • . . . Surprisingly, this function relies on the JmjC domain, indicating that there is either an additional role for the JmjC domain of Epe1 that is independent of enzymatic activity39, or an alternative enzymatic activity towards other non-histone substrates might exist . . .
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    • . . . Northern blot analysis indicates that PHF2 is ubiquitously expressed, and in situ hybridization has shown that the majority of PHF2 gene expression is concentrated in the embryonic neural tube and root ganglia in mice40 . . .
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    • . . . Although the wild-type function of PHF8 remains to be determined, mutations in human PHF8 cause inherited X-linked mental retardation (XLMR)41, 42 . . .
    • . . . Disease-causing mutations are predicted to result in truncations of PHF8, which remove a postulated NLS and presumably abrogate normal nuclear function41, 42 . . .
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    • . . . Although the wild-type function of PHF8 remains to be determined, mutations in human PHF8 cause inherited X-linked mental retardation (XLMR)41, 42 . . .
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    • . . . Mutations in genes that have roles in epigenetic regulation have previously been associated with XLMR44 . . .
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    • . . . JARID1A was initially discovered as a retinoblastoma (RB)-binding protein in a yeast two-hybrid screen45 . . .
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    • . . . Subsequent functional analysis revealed a role for JARID1A in the activation of RB-mediated transcription and, paradoxically, as a factor that antagonizes RB function under certain conditions46, 47 . . .
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    • . . . JARID1A also physically associates with several nuclear hormone receptors (NRs) to facilitate NR-mediated gene expression48 . . .
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    • . . . JARID1B transcripts are mainly found in the adult testis but are also transiently expressed during early development49, 50, 51 . . .
    • . . . JARID1B interacts with the developmentally important transcription factors BF1 and PAX9 to potentiate transcriptional repression52, and is frequently upregulated in breast cancers49, 51. . . .
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    • . . . JARID1B transcripts are mainly found in the adult testis but are also transiently expressed during early development49, 50, 51 . . .
    • . . . JARID1B interacts with the developmentally important transcription factors BF1 and PAX9 to potentiate transcriptional repression52, and is frequently upregulated in breast cancers49, 51. . . .
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    • . . . JARID1B interacts with the developmentally important transcription factors BF1 and PAX9 to potentiate transcriptional repression52, and is frequently upregulated in breast cancers49, 51. . . .
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    • . . . No cellular role has been defined for these proteins, although JARID1D was first identified as a male-specific antigen that contributes to the sex-specific tissue-transplantation rejection response53, 54 . . .
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    • . . . No cellular role has been defined for these proteins, although JARID1D was first identified as a male-specific antigen that contributes to the sex-specific tissue-transplantation rejection response53, 54 . . .
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    • . . . It is tempting to speculate that LID, the sole JARID1 orthologue in D. melanogaster, has evolved as part of the trithorax system to keep its target loci free of repressive H3K27 methylation, which is mediated by PcG proteins55 . . .
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    • . . . JARID2/JUMONJI has important roles in organogenesis; it functions as a transcriptional corepressor of cardiac genes, and controls cellular proliferation by interacting with transcription factors such as myocyte-specific enhancer factor 2, Nkx2.5, GATA4, and RB57, 58, 59, 60. . . .
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    • . . . JARID2/JUMONJI has important roles in organogenesis; it functions as a transcriptional corepressor of cardiac genes, and controls cellular proliferation by interacting with transcription factors such as myocyte-specific enhancer factor 2, Nkx2.5, GATA4, and RB57, 58, 59, 60. . . .
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    • . . . JARID2/JUMONJI has important roles in organogenesis; it functions as a transcriptional corepressor of cardiac genes, and controls cellular proliferation by interacting with transcription factors such as myocyte-specific enhancer factor 2, Nkx2.5, GATA4, and RB57, 58, 59, 60. . . .
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    • . . . JARID2/JUMONJI has important roles in organogenesis; it functions as a transcriptional corepressor of cardiac genes, and controls cellular proliferation by interacting with transcription factors such as myocyte-specific enhancer factor 2, Nkx2.5, GATA4, and RB57, 58, 59, 60. . . .
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    • . . . JHDM3A/JMJD2A was originally identified as a transcriptional repressor associated with the NCoR corepressor complex64, but has also been shown to physically interact with RB to repress E2F target genes65 . . .
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    • . . . Enzymes that contain SET domains, much like JmjC-domain proteins, fall into defined protein families, some of which have redundant modification-site specificity93 . . .
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    • . . . The characterized SET-domain proteins that have activity towards H3K9 (Suv39H1/2, ESET, RIZ, G9A and GLP1) and H3K36 (NSD1 (Ref. 1) and HYPB94) seem to use unique targeting mechanisms and result in the accumulation of different final modification states . . .
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    • . . . Of particular interest is the recent observation that EZH2, a PcG-group H3K27 methyltransferase, functions in maintaining the undifferentiated state of embryonic stem (ES) cells95, 96 . . .
  96. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349-353 , (2006) .
    • . . . Of particular interest is the recent observation that EZH2, a PcG-group H3K27 methyltransferase, functions in maintaining the undifferentiated state of embryonic stem (ES) cells95, 96 . . .
    • . . . When ES cells are induced to differentiate, a series of genes that contain H3K27 methylation, and are normally silenced, become activated concomitant with loss of H3K27 methylation96 . . .
  97. Letunic, I. et al. SMART 5: domains in the context of genomes and networks. Nucleic Acids Res. 34, D257-D260 , (2006) .
  98. Schultz, J., Milpetz, F., Bork, P. & Ponting, C. P. SMART, a simple modular architecture research tool: identification of signaling domains. Proc. Natl Acad. Sci. USA 95, 5857-5864 , (1998) .
  99. Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 32, D138-D141 , (2004) .
  100. Corpet, F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 16, 10881-10890 , (1988) .
  101. Kumar, S., Tamura, K. & Nei, M. MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform. 5, 150-163 , (2004) .
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