Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of histone methylation by demethylimination and demethylation

Nature Reviews Molecular Cell Biology volume 8, pages 307–318 (2007)Cite this article

Key Points

  • Modification of histone molecules within chromatin has a profound effect on genome structure and function. More specifically, methylation of histone arginine and lysine residues is involved in regulating transcription, epigenetic inheritance and controlling cell fate.

  • Until recently, histone methylation was considered a stable modification. The identification of a histone deiminase and histone demethylases has demonstrated that histone methylation can be dynamically regulated.

  • PADI4 can demethyliminate methylated arginine residues to produce citrulline. Although this reaction does not regenerate arginine, it reveals a mechanism by which arginine methylation can be antagonized.

  • LSD1 uses an amine oxidase reaction to directly remove histone lysine mono- and di-methylation. Removal of H3K4 and H3K9 methylation by LSD1 contributes to transcriptional repression and activation, respectively.

  • JmjC-domain-containing proteins encode a family of histone lysine demethylases that can remove all three methylation states. Members of this family have been shown to catalyse the removal of H3K4, H3K9 and H3K36 methylation.

  • Additional uncharacterized demethylation reaction mechanisms are likely to exist given the extensive complement of methylated histone residues and modification states.

Abstract

Histone methylation has important roles in regulating transcription, genome integrity and epigenetic inheritance. Historically, methylated histone arginine and lysine residues have been considered static modifications because of the low levels of methyl-group turnover in chromatin. The recent identification of enzymes that antagonize or remove histone methylation has changed this view and now the dynamic nature of these modifications is being appreciated. Here, we examine the enzymatic and structural basis for the mechanisms that these enzymes use to counteract histone methylation and provide insights into their substrate specificity and biological function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Methylation states of arginine and lysine residues in histones.
Figure 2: PADI4 is a methylarginine deiminase.
Figure 3: LSD1 is an H3K4 and H3K9 demethylase.
Figure 4: JmjC-domain-containing proteins encode histone lysine demethylases.

Similar content being viewed by others

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. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Wysocka, J., Allis, C. D. & Coonrod, S. Histone arginine methylation and its dynamic regulation. Front. Biosci. 11, 344–355 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Strahl, B. D. et al. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11, 996–1000 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Yu, M. C., Lamming, D. W., Eskin, J. A., Sinclair, D. A. & Silver, P. A. The role of protein arginine methylation in the formation of silent chromatin. Genes Dev. 20, 3249–3254 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Taverna, S. D. et al. Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Mol. Cell 24, 785–796 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. 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 

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

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shi, X. et al. Proteome-wide analysis in S. cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem. 282, 2450–2455 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Xiao, B. et al. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 421, 652–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).

    Article  CAS  PubMed  Google Scholar 

  19. Duerre, J. A. & Lee, C. T. In vivo methylation and turnover of rat brain histones. J. Neurochem. 23, 541–547 (1974).

    Article  CAS  PubMed  Google Scholar 

  20. Bannister, A. J. & Kouzarides, T. Reversing histone methylation. Nature 436, 1103–1106 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Allis, C. D., Bowen, J. K., Abraham, G. N., Glover, C. V. & Gorovsky, M. A. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell 20, 55–64 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. Saccani, S. & Natoli, G. Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. Genes Dev. 16, 2219–2224 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Annunziato, A. T., Eason, M. B. & Perry, C. A. Relationship between methylation and acetylation of arginine-rich histones in cycling and arrested HeLa cells. Biochemistry 34, 2916–2924 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Nakashima, K., Hagiwara, T. & Yamada, M. Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J. Biol. Chem. 277, 49562–49568 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Hagiwara, T., Nakashima, K., Hirano, H., Senshu, T. & Yamada, M. Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. Biochem. Biophys. Res. Commun. 290, 979–983 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004). References 28 and 29 show that PADI4 can antagonize histone arginine methylation by converting methylarginine to citrulline.

    Article  CAS  PubMed  Google Scholar 

  30. Kearney, P. L. et al. Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis. Biochemistry 44, 10570–10582 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Arita, K. et al. Structural basis for Ca2+-induced activation of human PAD4. Nature Struct. Mol. Biol. 11, 777–783 (2004).

    Article  CAS  Google Scholar 

  32. Lee, Y. H., Coonrod, S. A., Kraus, W. L., Jelinek, M. A. & Stallcup, M. R. Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc. Natl Acad. Sci. USA 102, 3611–3616 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, S., Benoiton, L. & Paik, W. K. ε-Alkyllysinase. Purification and properties of the enzyme. J. Biol. Chem. 239, 3790–3796 (1964).

    CAS  PubMed  Google Scholar 

  34. Paik, W. K. & Kim, S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun. 51, 781–788 (1973). The first demonstration that an enzymatic activity exists in mammalian tissues that can actively demethylate calf thymus histones.

    Article  CAS  PubMed  Google Scholar 

  35. Paik, W. K. & Kim, S. ε-alkyllysinase. New assay method, purification, and biological significance. Arch. Biochem. Biophys. 165, 369–378 (1974).

    Article  CAS  PubMed  Google Scholar 

  36. Hakimi, M. A., Dong, Y., Lane, W. S., Speicher, D. W. & Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278, 7234–7239 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001). Co-REST-containing histone deacetylase complexes are shown to bind FAD and house the amine-oxidase-domain-containing protein LSD1/kiaa0601. The authors speculate that this domain might covalently modify chromatin.

    Article  CAS  PubMed  Google Scholar 

  38. Lee, M. G. et al. Functional interplay between histone demethylase and deacetylase enzymes. Mol. Cell Biol. 26, 6395–6402 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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). References 39 and 44 show that the interaction between LSD1 and Co-REST is important for nucleosomal demethylation.

    Article  CAS  PubMed  Google Scholar 

  40. Shi, Y. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004). The authors identify the first histone lysine demethylase and demonstrate its role in transcriptional repression.

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Chen, Y. et al. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc. Natl Acad. Sci. USA 103, 13956–13961 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stavropoulos, P., Blobel, G. & Hoelz, A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nature Struct. Mol. Biol. 13, 626–632 (2006).

    Article  CAS  Google Scholar 

  47. Yang, M. et al. Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol. Cell 23, 377–387 (2006). References 45–47 report the crystal structure of LSD1, and reference 47 also reports on the crystal structure of LSD1–Co-REST, providing insight into the potential mechanisms for nucleosomal demethylation.

    Article  CAS  PubMed  Google Scholar 

  48. Forneris, F., Binda, C., Vanoni, M. A., Battaglioli, E. & Mattevi, A. Human histone demethylase LSD1 reads the histone code. J. Biol. Chem. 280, 41360–41365 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Ballas, N. et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron 31, 353–365 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006). Using an unbiased biochemical approach, a JmjC-domain-containing demethylase with specificity toward H3K9 was identified, verifying that the JmjC domain is a histone-demethylase signature motif.

    Article  CAS  PubMed  Google Scholar 

  52. Jarriault, S. & Greenwald, I. Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans. Genes Dev. 16, 2713–2728 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Eimer, S., Lakowski, B., Donhauser, R. & Baumeister, R. Loss of spr-5 bypasses the requirement for the C. elegans presenilin sel-12 by derepressing hop-1. EMBO J. 21, 5787–5796 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dallman, J. E., Allopenna, J., Bassett, A., Travers, A. & Mandel, G. A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation. J. Neurosci. 24, 7186–7193 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nicolas, E. et al. Fission yeast homologs of human histone h3 lysine 4 demethylase regulate a common set of genes with diverse functions. J. Biol. Chem. 281, 35983–35988 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Trewick, S. C., Henshaw, T. F., Hausinger, R. P., Lindahl, T. & Sedgwick, B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 419, 174–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Falnes, P. O., Johansen, R. F. & Seeberg, E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 419, 178–182 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. 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 on the basis of the function of the fission yeast JmjC-domain protein Epe1 in regulating silent chromatin structure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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. This study shows that the JmjC domain is a signature motif for histone demethylases.

    Article  CAS  PubMed  Google Scholar 

  60. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Gearhart, M. D., Corcoran, C. M., Wamstad, J. A. & Bardwell, V. J. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol. Cell Biol. 26, 6880–6889 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xiao, T. et al. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev. 17, 654–663 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Krogan, N. J. et al. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol. Cell Biol. 23, 4207–4218 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, B., Howe, L., Anderson, S., Yates, J. R., 3rd & Workman, J. L. The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymerase II. J. Biol. Chem. 278, 8897–8903 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Li, J., Moazed, D. & Gygi, S. P. Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation. J. Biol. Chem. 277, 49383–49388 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Schaft, D. et al. The histone 3 lysine 36 methyltransferase, SET2, is involved in transcriptional elongation. Nucleic Acids Res. 31, 2475–2482 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. Keogh, M. C. et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593–605 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. Joshi, A. A. & Struhl, K. Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Mol. Cell 20, 971–978 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pena, P. V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Pokholok, D. K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  76. 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 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. 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 

  80. Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006). References 77–80 show that the JHDM3/JMJD2 histone demethylase enzymes are capable of removing the tri-methyl-modification state.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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 

  82. Vakoc, C. R. et al. Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol. Cell 17, 453–462 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Vakoc, C. R., Sachdeva, M. M., Wang, H. & Blobel, G. A. Profile of histone lysine methylation across transcribed mammalian chromatin. Mol. Cell Biol. 26, 9185–9195 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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 

  85. Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 22 Feb 2007 (doi: 10.1016/j.cell.2007.02.013).

  86. Lee, N. et al. The trithorax group protein Lid is a trimethyl-H3K4 demethylase. Nature Struct. Mol. Biol. (in the press).

  87. Liang, G., Klose, R. J., Gardener, K. E. & Zhang, Y. Yeast Jhd2 is an H3-K4 tri-methyl demethylase. Nature Struct. Mol. Biol. 18 Feb 2007 (doi: 10.1038/nsmb1204). References 85–87 show that the JARID1 family of JmjC-domain-containing proteins are H3K4 demethylases with the capacity to remove the tri-methyl-modification state.

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

    Article  CAS  PubMed  Google Scholar 

  89. Jensen, L. R. et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am. J. Hum. Genet. 76, 227–236 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. 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 

  91. 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 

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

    Article  CAS  PubMed  Google Scholar 

  93. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. 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 

  98. Issaeva, I. et al. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol. Cell Biol. (2006).

  99. Klymenko, T. & Muller, J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 5, 373–377 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Papp, B. & Muller, J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 20, 2041–2054 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Poux, S., Horard, B., Sigrist, C. J. & Pirrotta, V. The Drosophila Trithorax protein is a coactivator required to prevent re-establishment of polycomb silencing. Development 129, 2483–2493 (2002).

    CAS  PubMed  Google Scholar 

  102. Zhang, L., Schroeder, S., Fong, N. & Bentley, D. L. Altered nucleosome occupancy and histone H3K4 methylation in response to 'transcriptional stress'. EMBO J. 24, 2379–2390 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Katan-Khaykovich, Y. & Struhl, K. Heterochromatin formation involves changes in histone modifications over multiple cell generations. EMBO J. 24, 2138–2149 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Morillon, A., Karabetsou, N., Nair, A. & Mellor, J. Dynamic lysine methylation on histone H3 defines the regulatory phase of gene transcription. Mol. Cell 18, 723–734 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. van Leeuwen, F., Gafken, P. R. & Gottschling, D. E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).

    CAS  PubMed  Google Scholar 

  106. Ng, H. H., Ciccone, D. N., Morshead, K. B., Oettinger, M. A. & Struhl, K. Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc. Natl Acad. Sci. USA 100, 1820–1825 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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 

  108. Kourmouli, N. et al. Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J. Cell Sci. 117, 2491–2501 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Sims, J. K., Houston, S. I., Magazinnik, T. & Rice, J. C. A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin. J. Biol. Chem. 281, 12760–12766 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Dunwell, J. M., Culham, A., Carter, C. E., Sosa-Aguirre, C. R. & Goodenough, P. W. Evolution of functional diversity in the cupin superfamily. Trends Biochem. Sci. 26, 740–746 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Clissold, P. M. & Ponting, C. P. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2β. Trends Biochem. Sci. 26, 7–9 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Chinenov, Y. A second catalytic domain in the Elp3 histone acetyltransferases: a candidate for histone demethylase activity? Trends Biochem. Sci. 27, 115–117 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Paraskevopoulou, C., Fairhurst, S. A., Lowe, D. J., Brick, P. & Onesti, S. The elongator subunit Elp3 contains a Fe4S4 cluster and binds S-adenosylmethionine. Mol. Microbiol. 59, 795–806 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Marsh, E. N., Patwardhan, A. & Huhta, M. S. S-adenosylmethionine radical enzymes. Bioorg. Chem. 32, 326–340 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. 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 

  116. Ladurner, A. G. Rheostat control of gene expression by metabolites. Mol. Cell 24, 1–11 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tanner, K. G., Landry, J., Sternglanz, R. & Denu, J. M. Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl Acad. Sci. USA 97, 14178–14182 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Torres-Padilla, M. E., Parfitt, D. E., Kouzarides, T. & Zernicka-Goetz, M. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214–218 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dodge, J. E., Kang, Y. K., Beppu, H., Lei, H. & Li, E. Histone H3-K9 methyltransferase ESET is essential for early development. Mol. Cell Biol. 24, 2478–2486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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 

  125. Luo, Y. et al. Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry 45, 11727–11736 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Stone, E. M., Schaller, T. H., Bianchi, H., Person, M. D. & Fast, W. Inactivation of two diverse enzymes in the amidinotransferase superfamily by 2-chloroacetamidine: dimethylargininase and peptidylarginine deiminase. Biochemistry 44, 13744–13752 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–567 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Culhane, J. C. et al. A mechanism-based inactivator for histone demethylase LSD1. J. Am. Chem. Soc. 128, 4536–4537 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Forneris, F. et al. A highly specific mechanism of histone H3-K4 recognition by histone demethylase LSD1. J. Biol. Chem. 281, 35289–35295 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Klose, R. J. et al. Demethylation of histone H3K36 and H3K9 by Rph1: a vestige of an H3K9 methylation system in Saccharomyces cerevisiae? Mol. Cell Biol. (in the press).

  131. Seward, D. J. et al. Demethylation of trimethylated histone H3 Lys 4 in vivo by JARID1 JmjC proteins. Nature Struct. Mol. Biol. 18 Feb 2007 (doi: 10.1038/nsmb1200).

  132. Secombe, J., Li, L., Carlos, L. & Eisenman, R. N. The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev. 20 Feb 2007 (doi: 10.1101/gad.1523007).

  133. Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri- and dimethylated lysine 4 on histone 3. Cell 22 Feb 2007 (doi: 10.1016/j.cell.2007.02.003).

  134. Lee, M. G., Norman, J., Shilatifard, A. & Shiekhattar, R. Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a Polycomb-like protein. Cell 22 Feb 2007 (doi: 10.1016/j.cell.2007.02.004).

  135. Iwase, S. et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 22 Feb 2007 (doi: 10.1016/j.cell.2007.02.017).

Download references

Acknowledgements

We would like to thank H. Yu, G. Zhang, R. Xu and Y. Huang for providing structural images. We also acknowledge K. Gardner for critical reading of the manuscript. We apologize to colleagues whose work we were not able to cover due to space limitations. R.J.K is funded by the Canadian Institutes of Health Research. Work in the Zhang laboratory is funded by grants from the National Institutes of Health and Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599–7295, North Carolina, USA

    Robert J. Klose & Yi Zhang

Authors
  1. Robert J. Klose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Yi Zhang's homepage

Glossary

SET domain

A sequence motif (named after Su(var)3–9, Enhancer of Zeste, Trithorax) that is found in several chromatin-associated proteins, including members of both the Trithorax group and Polycomb group.

SANT domain

The SANT domain (named after 'switching-defective protein 3 (Swi3), adaptor 2 (Ada2), nuclear receptor co-repressor (N-CoR), transcription factor ((TF)IIIB)) is a 50-amino-acid motif that is present in nuclear receptor co-repressors and many chromatin-remodelling complexes.

PHD domain

(Plant homeodomain). A zinc-binding domain found in many chromatin-associated proteins. Some PHD-domain-containing proteins have been shown to recognize methylated lysine residues in chromatin.

Tudor domain

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.

X-linked mental retardation

A term broadly used in reference to a group of inherited mental retardations with primary genetic defects mapping to the X chromosome.

Trithorax

Antagonists of Polycomb-group (PcG) proteins that maintain the active state of gene expression, whereas PcG proteins counteract this activation by repressing gene expression.

Polycomb group

(PcG). A class of proteins, originally described in Drosophila melanogaster, that maintain the stable and heritable repression of several genes, including the homeotic genes.

S-adenosylmethionine

(SAM). A biological compound that is involved in methyl-group transfer in living cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klose, R., Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8, 307–318 (2007). https://doi.org/10.1038/nrm2143

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2143

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing