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JmjC-domain-containing proteins and histone demethylation

Key Points

  • 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.

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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Figure 1: Chemical mechanism by which three distinct classes of enzymes antagonize histone methylation.
Figure 2: The JmjC domain contains residues required for Fe(II) and αKG binding.
Figure 3: Phylogenetic relationship of JmjC-domain-containing proteins from model organisms.
Figure 4: JHDM1 proteins are H3K36 demethylases.
Figure 5: PHF2/PHF8 proteins are related to the JHDM1 histone demethylases.
Figure 6: The JARID1/2 group contains potentially active enzymes.
Figure 7: The JHDM3/JMJD2 proteins are H3K9/K36 demethylases.
Figure 8: UTX/UTY proteins are poorly characterized proteins with conserved JmjC domains.
Figure 9: JHDM2 proteins are H3K9 demethylases.

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References

  1. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nature Rev. Mol. Cell Biol. 6, 838–849 (2005).

    Article  CAS  Google Scholar 

  2. Vakoc, C. R., Mandat, S. A., Olenchock, B. A. & Blobel, G. A. Histone H3 lysine 9 methylation and HP1γ are associated with transcription elongation through mammalian chromatin. Mol. Cell 19, 381–391 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Carrozza, M. J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromodomain. Nature 410, 120–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 91–95 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004). References 7 and 8 identify PADI4 as the first enzyme capable of antagonizing histone arginine methylation.

    Article  CAS  PubMed  Google Scholar 

  9. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004). Identifies the first true histone demethylase enzyme, LSD1, which utilizes flavin as a cofactor to carry out an oxidative demethylation reaction.

    Article  CAS  PubMed  Google Scholar 

  10. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  12. Shi, Y. J. et al. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 857–864 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Tsukada, Y. et al. Histone demethylation by a family of JmjC-domain-containing proteins. Nature 439, 811–816 (2006). The authors used a novel in vitro histone demethylase assay to biochemically purify and characterize the first JmjC-domain-containing histone demethylase enzyme.

    Article  CAS  PubMed  Google Scholar 

  14. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006). The authors biochemically purified a novel JmjC-domain-containing histone H3K9 demethylase and demonstrated its role in androgen receptor-mediated gene activation.

    Article  CAS  PubMed  Google Scholar 

  15. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Klose, R. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and 36. Nature 442, 312–316 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006). References 15 to 18 demonstrate that the JHDM3/JMJD2 histone demethylase enzymes are capable of removing the trimethyl modification state.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Clissold, P. M. & Ponting, C. P. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2β. Trends Biochem. Sci. 26, 7–9 (2001). The authors identify bioinformatic and structural similarities between metalloenzymes and JmjC-domain-containing proteins.

    Article  CAS  PubMed  Google Scholar 

  20. Takeuchi, T. et al. Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. Genes Dev. 9, 1211–1222 (1995). 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.

    Article  CAS  PubMed  Google Scholar 

  21. Balciunas, D. & Ronne, H. Evidence of domain swapping within the Jumonji family of transcription factors. Trends Biochem. Sci. 25, 274–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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 (2002). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Trewick, S. C., McLaughlin, P. J. & Allshire, R. C. Methylation: lost in hydroxylation? EMBO Rep. 6, 315–320 (2005). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Elkins, J. M. et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF1α. J. Biol. Chem. 278, 1802–1806 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, Z. et al. Structural insights into histone demethylation by JMJD2 family members. Cell 125, 691–702 (2006). A report of the first crystal structure of the enzymatic domain of an active JmjC-domain-containing histone demethylase, JHDM3A/JMJD2A.

    Article  CAS  PubMed  Google Scholar 

  29. Clifton, I. J. et al. Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins. J. Inorg. Biochem. 100, 644–669 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Chenna, R. et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res. 31, 3497–3500 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huelsenbeck, J. P. & Ronquist, F. MrBayes: Bayesian inference of phylogenetic trees. Bioinformatics 17, 754–755 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Ronquist, F. & Huelsenbeck, J. P. MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19, 1572–1574 (2003).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ayoub, N. et al. A novel JmjC domain protein modulates heterochromatization in fission yeast. Mol. Cell. Biol. 23, 4356–4370 (2003). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jorgensen, H. F., Ben-Porath, I. & Bird, A. P. MBD1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol. Cell. Biol. 24, 3387–3395 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  39. Zofall, M. & Grewal, S. I. Swi6/HP1 recruits a JmjC-domain protein to facilitate transcription of heterochromatic repeats. Mol. Cell 22, 681–692 (2006). The authors demonstrate that Epe1 functions in heterochromatin to promote Pol II accessibility by counteracting repressive chromatin.

    Article  CAS  PubMed  Google Scholar 

  40. Hasenpusch-Theil, K. et al. PHF2, a novel PHD finger gene located on human chromosome 9q22. Mamm. Genome 10, 294–298 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Laumonnier, F. et al. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J. Med. Genet. 42, 780–786 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Siderius, L. E. et al. X linked mental retardation associated with cleft lip/palate maps to Xp11.3–q21.3. Am. J. Med. Genet. 85, 216–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Fernandez, A. G. et al. New genes with roles in the Caenorhabditis elegans embryo revealed using RNAi of ovary-enriched ORFeome clones. Genome Res. 15, 250–259 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chelly, J. & Mandel, J. L. Monogenic causes of X linked mental retardation. Nature Rev. Genet. 2, 669–680 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Defeo-Jones, D. et al. Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature 352, 251–254 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Kratzke, R. A. et al. Partial inactivation of the RB product in a family with incomplete penetrance of familial retinoblastoma and benign retinal tumors. Oncogene 9, 1321–1326 (1994).

    CAS  PubMed  Google Scholar 

  47. Benevolenskaya, E. V., Murray, H. L., Branton, P., Young, R. A. & Kaelin, W. G. Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol. Cell 18, 623–635 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Chan, S. W. & Hong, W. Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription. J. Biol. Chem. 276, 28402–28412 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Lu, P. J. et al. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically upregulated in breast cancer. J. Biol. Chem. 274, 15633–15645 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Madsen, B. et al. PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis. Chromosoma 112, 124–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Madsen, B. et al. Characterisation and developmental expression of mouse Plu-1, a homologue of a human nuclear protein (PLU-1) which is specifically upregulated in breast cancer. Mech. Dev. 119, S239–S246 (2002).

    Article  PubMed  Google Scholar 

  52. Tan, K. et al. Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. J. Biol. Chem. 278, 20507–20513 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, W. et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 269, 1588–1590 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Scott, D. M. et al. Identification of a mouse male-specific transplantation antigen, H-Y. Nature 376, 695–698 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Gildea, J. J., Lopez, R. & Shearn, A. A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2. Genetics 156, 645–663 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Jung, J., Mysliwiec, M. R. & Lee, Y. Roles of JUMONJI in mouse embryonic development. Dev. Dyn. 232, 21–32 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Takeuchi, T., Kojima, M., Nakajima, K. & Kondo, S. Jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background. Mech. Dev. 86, 29–38 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Jung, J., Kim, T. G., Lyons, G. E., Kim, H. R. & Lee, Y. Jumonji regulates cardiomyocyte proliferation via interaction with retinoblastoma protein. J. Biol. Chem. 280, 30916–30923 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Kim, T. G., Chen, J., Sadoshima, J. & Lee, Y. Jumonji represses atrial natriuretic factor gene expression by inhibiting transcriptional activities of cardiac transcription factors. Mol. Cell. Biol. 24, 10151–10160 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim, T. G., Jung, J., Mysliwiec, M. R., Kang, S. & Lee, Y. Jumonji represses alpha-cardiac myosin heavy chain expression via inhibiting MEF2 activity. Biochem. Biophys. Res. Commun. 329, 544–553 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Katoh, M. & Katoh, M. Identification and characterization of JMJD2 family genes in silico. Int. J. Oncol. 24, 1623–1628 (2004).

    CAS  PubMed  Google Scholar 

  63. Yang, Z. Q. et al. Identification of a novel gene, GASC1, within an amplicon at 9p23–24 frequently detected in esophageal cancer cell lines. Cancer Res. 60, 4735–4739 (2000).

    CAS  PubMed  Google Scholar 

  64. Zhang, D., Yoon, H. G. & Wong, J. JMJD2A is a novel N–CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Mol. Cell. Biol. 25, 6404–6414 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gray, S. G. et al. Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein. J. Biol. Chem. 280, 28507–28518 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Kim, J. et al. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep. 7, 397–403 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Huang, Y., Fang, J., Bedford, M. T., Zhang, Y. & Xu, R. M. Recognition of hstone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312, 748–751 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Bannister, A. J. et al. Spatial distribution of di- and trimethyl lysine 36 of histone H3 at active genes. J. Biol. Chem. 280, 17732–17736 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Jang, Y. K., Wang, L. & Sancar, G. B. RPH1 and GIS1 are damage-responsive repressors of PHR1. Mol. Cell. Biol. 19, 7630–7638 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Greenfield, A. et al. An H-YDb epitope is encoded by a novel mouse Y chromosome gene. Nature Genet. 14, 474–478 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Greenfield, A. et al. The UTX gene escapes X inactivation in mice and humans. Hum. Mol. Genet. 7, 737–742 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Hu, Z. et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene 20, 6946–6954 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Cachon-Gonzalez, M. B. et al. Structure and expression of the hairless gene of mice. Proc. Natl Acad. Sci. USA 91, 7717–7721 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ahmad, W. et al. Alopecia universalis associated with a mutation in the human hairless gene. Science 279, 720–724 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Potter, G. B. et al. The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes Dev. 15, 2687–2701 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hoog, C., Schalling, M., Grunder-Brundell, E. & Daneholt, B. Analysis of a murine male germ cell-specific transcript that encodes a putative zinc finger protein. Mol. Reprod. Dev. 30, 173–181 (1991).

    Article  CAS  PubMed  Google Scholar 

  77. Lee, J. W., Choi, H. S., Gyuris, J., Brent, R. & Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol. Endocrinol. 9, 243–254 (1995).

    CAS  PubMed  Google Scholar 

  78. Metzen, E. et al. Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing. J. Cell Sci. 116, 1319–1326 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Tsuneoka, M., Koda, Y., Soejima, M., Teye, K. & Kimura, H. A novel myc target gene, mina53, that is involved in cell proliferation. J. Biol. Chem. 277, 35450–35459 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Zhang, Y. et al. The human mineral dust-induced gene, MDIG, is a cell growth regulating gene associated with lung cancer. Oncogene 24, 4873–4882 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Eilbracht, J., Kneissel, S., Hofmann, A. & Schmidt-Zachmann, M. S. Protein NO52 — a constitutive nucleolar component sharing high sequence homologies to protein NO66. Eur. J. Cell Biol. 84, 279–294 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Eilbracht, J. et al. NO66, a highly conserved dual location protein in the nucleolus and in a special type of synchronously replicating chromatin. Mol. Biol. Cell 15, 1816–1832 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pickard, R. T., Strifler, B. A., Kramer, R. M. & Sharp, J. D. Molecular cloning of two new human paralogs of 85 kDa cytosolic phospholipase A2. J. Biol. Chem. 274, 8823–8831 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Hirabayashi, T., Murayama, T. & Shimizu, T. Regulatory mechanism and physiological role of cytosolic phospholipase A2. Biol. Pharm. Bull. 27, 1168–1173 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, C., Gilmont, R. R., Benndorf, R. & Welsh, M. J. Identification and characterization of a novel protein from Sertoli cells, PASS1, that associates with mammalian small stress protein hsp27. J. Biol. Chem. 275, 18724–18731 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Bodmer, D., Schepens, M., Eleveld, M. J., Schoenmakers, E. F. & Geurts van Kessel, A. Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21). Genes Chromosomes Cancer 38, 107–116 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Kunisaki, Y. et al. Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor. Blood 103, 3362–3364 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Bose, J. et al. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J. Biol. 3, 15 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Cui, P., Qin, B., Liu, N., Pan, G. & Pei, D. Nuclear localization of the phosphatidylserine receptor protein via multiple nuclear localization signals. Exp. Cell Res. 293, 154–163 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Cikala, M. et al. The phosphatidylserine receptor from Hydra is a nuclear protein with potential Fe(II) dependent oxygenase activity. BMC Cell Biol. 5, 26 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sun, X. J. et al. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J. Biol. Chem. 280, 35261–35271 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. O'Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Letunic, I. et al. SMART 5: domains in the context of genomes and networks. Nucleic Acids Res. 34, D257–D260 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 32, D138–D141 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Corpet, F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 16, 10881–10890 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kumar, S., Tamura, K. & Nei, M. MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform. 5, 150–163 (2004).

    Article  CAS  PubMed  Google Scholar 

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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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DATABASES

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FURTHER INFORMATION

ClustalW

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Glossary

Cupin

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

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

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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