Dynamics of Histone Lysine Methylation: Structures of Methyl Writers and Erasers

  • Anup K. Upadhyay
  • Xiaodong Cheng
Part of the Progress in Drug Research book series (PDR, volume 67)


In Eukarya, the packaging of DNA into chromatin provides a barrier that allows for regulation of access to the genome. Chromatin is refractory to processes acting on DNA. ATP-dependent chromatin remodeling machines and histone-modifying complexes can overcome this barrier (or strengthen it in silencing processes). Both components of chromatin (DNA and histones) are subject to postsynthetic covalent modifications, including methylation of lysines (the focus of this chapter). These lysine marks are generated by a host of histone lysine methyltransferases (writers) and can be removed by histone lysine demethylases (erasers). Importantly, epigenetic modifications impact chromatin structure directly or can be read by effector regulatory modules. Here, we summarize current knowledge on structural and functional properties of various histone lysine methyltransfereases and demethylases, with emphasis on their importance as druggable targets.


Methyl Mark Histone Code Histone Lysine Lysine Methylation Demethylase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The work in the Cheng laboratory was supported by grants GM06860 and DK082678 from the National Institutes of Health (NIH). X.C. is a Georgia Research Alliance Eminent Scholar.


  1. 1.
    Martens JH, O’Sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005) The profile of repeat-associated histone lysine methylation states in the mouse epigenome. Embo J 24:800–812PubMedGoogle Scholar
  2. 2.
    Klose RJ, Kallin EM, Zhang Y (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7:715–727PubMedGoogle Scholar
  3. 3.
    Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8:829–833PubMedGoogle Scholar
  4. 4.
    Li H, Ilin S, Wang W, Duncan EM, Wysocka J, Allis CD, Patel DJ (2006) Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442:91–95PubMedGoogle Scholar
  5. 5.
    Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, Wu C, Allis CD (2006) A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442:86–90PubMedGoogle Scholar
  6. 6.
    Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410:120–124PubMedGoogle Scholar
  7. 7.
    Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410:116–120PubMedGoogle Scholar
  8. 8.
    Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ (2009) Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461(7265):762–767PubMedGoogle Scholar
  9. 9.
    Collins RE, Northrop JP, Horton JR, Lee DY, Zhang X, Stallcup MR, Cheng X (2008) The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat Struct Mol Biol 15:245–250PubMedGoogle Scholar
  10. 10.
    Zhang K, Mosch K, Fischle W, Grewal SI (2008) Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin. Nat Struct Mol Biol 15:381–388PubMedGoogle Scholar
  11. 11.
    Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6:838–849PubMedGoogle Scholar
  12. 12.
    Ng SS, Yue WW, Oppermann U, Klose RJ (2009) Dynamic protein methylation in chromatin biology. Cell Mol Life Sci 66:407–422PubMedGoogle Scholar
  13. 13.
    Schneider R, Bannister AJ, Kouzarides T (2002) Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem Sci 27:396–402PubMedGoogle Scholar
  14. 14.
    Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M (2009) The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4:1568–1582PubMedGoogle Scholar
  15. 15.
    Spannhoff A, Sippl W, Jung M (2009) Cancer treatment of the future: inhibitors of histone methyltransferases. Int J Biochem Cell Biol 41:4–11PubMedGoogle Scholar
  16. 16.
    van Leeuwen F, Gafken PR, Gottschling DE (2002) Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109:745–756PubMedGoogle Scholar
  17. 17.
    Min J, Feng Q, Li Z, Zhang Y, Xu RM (2003) Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112:711–723PubMedGoogle Scholar
  18. 18.
    Sawada K, Yang Z, Horton JR, Collins RE, Zhang X, Cheng X (2004) Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. J Biol Chem 279:43296–43306PubMedGoogle Scholar
  19. 19.
    Cheng X, Collins RE, Zhang X (2005) Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomol Struct 34:267–294PubMedGoogle Scholar
  20. 20.
    Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6:227PubMedGoogle Scholar
  21. 21.
    Qian C, Zhou MM (2006) SET domain protein lysine methyltransferases: structure, specificity and catalysis. Cell Mol Life Sci 63:2755–2763PubMedGoogle Scholar
  22. 22.
    Couture JF, Trievel RC (2006) Histone-modifying enzymes: encrypting an enigmatic epigenetic code. Curr Opin Struct Biol 16:753–760PubMedGoogle Scholar
  23. 23.
    Cheng X, Zhang X (2007) Structural dynamics of protein lysine methylation and demethylation. Mutat Res/Fundam Mol Mech Mutagen 618:102–115Google Scholar
  24. 24.
    Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406:593–599PubMedGoogle Scholar
  25. 25.
    Volkel P, Angrand PO (2007) The control of histone lysine methylation in epigenetic regulation. Biochimie 89:1–20PubMedGoogle Scholar
  26. 26.
    Zhang X, Yang Z, Khan SI, Horton JR, Tamaru H, Selker EU, Cheng X (2003) Structural basis for the product specificity of histone lysine methyltransferases. Mol Cell 12:177–185PubMedGoogle Scholar
  27. 27.
    Collins RE, Tachibana M, Tamaru H, Smith KM, Jia D, Zhang X, Selker EU, Shinkai Y, Cheng X (2005) In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J Biol Chem 280:5563–5570PubMedGoogle Scholar
  28. 28.
    Couture JF, Dirk LM, Brunzelle JS, Houtz RL, Trievel RC (2008) Structural origins for the product specificity of SET domain protein methyltransferases. Proc Natl Acad Sci USA 105:20659–20664PubMedGoogle Scholar
  29. 29.
    Takahashi YH, Lee JS, Swanson SK, Saraf A, Florens L, Washburn MP, Trievel RC, Shilatifard A (2009) Regulation of H3K4 trimethylation via Cps40 (Spp 1) of COMPASS is monoubiquitination independent: implication for a Phe/Tyr switch by the catalytic domain of Set1. Mol Cell Biol 29:3478–3486PubMedGoogle Scholar
  30. 30.
    Zhang X, Tamaru H, Khan SI, Horton JR, Keefe LJ, Selker EU, Cheng X (2002) Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111:117–127PubMedGoogle Scholar
  31. 31.
    Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ (2003) Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 421:652–656PubMedGoogle Scholar
  32. 32.
    Rathert P, Dhayalan A, Murakami M, Zhang X, Tamas R, Jurkowska R, Komatsu Y, Shinkai Y, Cheng X, Jeltsch A (2008) Protein lysine methyltransferase G9a acts on non-histone targets. Nat Chem Biol 4:344–346PubMedGoogle Scholar
  33. 33.
    Couture JF, Collazo E, Hauk G, Trievel RC (2006) Structural basis for the methylation site specificity of SET7/9. Nat Struct Mol Biol 13:140–146PubMedGoogle Scholar
  34. 34.
    Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D (2004) Regulation of p53 activity through lysine methylation. Nature 432:353–360PubMedGoogle Scholar
  35. 35.
    Kouskouti A, Scheer E, Staub A, Tora L, Talianidis I (2004) Gene-specific modulation of TAF10 function by SET9-mediated methylation. Mol Cell 14:175–182PubMedGoogle Scholar
  36. 36.
    Subramanian K, Jia D, Kapoor-Vazirani P, Powell DR, Collins RE, Sharma D, Peng J, Cheng X, Vertino PM (2008) Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol Cell 30:336–347PubMedGoogle Scholar
  37. 37.
    Esteve PO, Chin HG, Benner J, Feehery GR, Samaranayake M, Horwitz GA, Jacobsen SE, Pradhan S (2009) Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Proc Natl Acad Sci USA 106:5076–5081PubMedGoogle Scholar
  38. 38.
    Pless O, Kowenz-Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh MJ, Leutz A (2008) G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. J Biol Chem 283:26357–26363PubMedGoogle Scholar
  39. 39.
    Sampath SC, Marazzi I, Yap KL, Sampath SC, Krutchinsky AN, Mecklenbrauker I, Viale A, Rudensky E, Zhou MM, Chait BT, Tarakhovsky A (2007) Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell 27:596–608PubMedGoogle Scholar
  40. 40.
    Huang J, Berger SL (2008) The emerging field of dynamic lysine methylation of non-histone proteins. Curr Opin Genet Dev 18:152–158PubMedGoogle Scholar
  41. 41.
    Jenuwein T (2006) The epigenetic magic of histone lysine methylation. Febs J 273:3121–3135PubMedGoogle Scholar
  42. 42.
    Grewal SI, Jia S (2007) Heterochromatin revisited. Nat Rev Genet 8:35–46PubMedGoogle Scholar
  43. 43.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791PubMedGoogle Scholar
  44. 44.
    Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev 19:815–826PubMedGoogle Scholar
  45. 45.
    McGarvey KM, Fahrner JA, Greene E, Martens J, Jenuwein T, Baylin SB (2006) Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res 66:3541–3549PubMedGoogle Scholar
  46. 46.
    Wozniak RJ, Klimecki WT, Lau SS, Feinstein Y, Futscher BW (2007) 5-Aza-2′-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 26:77–90PubMedGoogle Scholar
  47. 47.
    Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, Redkar S, Jones PA (2007) Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 67:6400–6408PubMedGoogle Scholar
  48. 48.
    Kubicek S, O’Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K, Kowalski JA, Homon CA, Kelly TA, Jenuwein T (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25:473–481PubMedGoogle Scholar
  49. 49.
    Chang Y, Zhang X, Horton JR, Upadhyay AK, Spannhoff A, Liu J, Snyder JP, Bedford MT, Cheng X (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 16:312–317PubMedGoogle Scholar
  50. 50.
    Trojer P, Zhang J, Yonezawa M, Schmidt A, Zheng H, Jenuwein T, Reinberg D (2009) Dynamic histone H1 isotype 4 methylation and demethylation by histone lysine methyltransferase G9a/KMT1C and the jumonji domain-containing JMJD2/KDM4 proteins. J Biol Chem 284:8395–8405PubMedGoogle Scholar
  51. 51.
    Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S (2008) A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2:525–528PubMedGoogle Scholar
  52. 52.
    Xu Y, Shi Y, Ding S (2008) A chemical approach to stem-cell biology and regenerative medicine. Nature 453:338–344PubMedGoogle Scholar
  53. 53.
    Feng B, Ng JH, Heng JC, Ng HH (2009) Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell 4:301–312PubMedGoogle Scholar
  54. 54.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  55. 55.
    Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y (2006) G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol 8:188–194PubMedGoogle Scholar
  56. 56.
    Liu F, Chen X, Allali-Hassani A, Quinn AM, Wasney GA, Dong A, Barsyte D, Kozieradzki I, Senisterra G, Chau I, Siarheyeva A, Kireev DB, Jadhav A, Herold JM, Frye SV, Arrowsmith CH, Brown PJ, Simeonov A, Vedadi M, Jin J (2009) Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 52(24):7950–7953PubMedGoogle Scholar
  57. 57.
    Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953PubMedGoogle Scholar
  58. 58.
    Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schule R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–439PubMedGoogle Scholar
  59. 59.
    Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL (2007) p53 is regulated by the lysine demethylase LSD1. Nature 449:105–108PubMedGoogle Scholar
  60. 60.
    Karytinos A, Forneris F, Profumo A, Ciossani G, Battaglioli E, Binda C, Mattevi A (2009) A novel mammalian flavin-dependent histone demethylase. J Biol Chem 284:17775–17782PubMedGoogle Scholar
  61. 61.
    Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, Xu G, Li E, Chen T (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461(7262):415–418PubMedGoogle Scholar
  62. 62.
    Shi Y, Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25:1–14PubMedGoogle Scholar
  63. 63.
    Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y (2005) Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 19:857–864PubMedGoogle Scholar
  64. 64.
    Lee MG, Wynder C, Cooch N, Shiekhattar R (2005) An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437:432–435PubMedGoogle Scholar
  65. 65.
    Tochio N, Umehara T, Koshiba S, Inoue M, Yabuki T, Aoki M, Seki E, Watanabe S, Tomo Y, Hanada M, Ikari M, Sato M, Terada T, Nagase T, Ohara O, Shirouzu M, Tanaka A, Kigawa T, Yokoyama S (2006) Solution structure of the SWIRM domain of human histone demethylase LSD1. Structure14:457–468PubMedGoogle Scholar
  66. 66.
    Forneris F, Binda C, Vanoni MA, Battaglioli E, Mattevi A (2005) Human histone demethylase LSD1 reads the histone code. J Biol Chem 280:41360–41365PubMedGoogle Scholar
  67. 67.
    Chen Y, Yang Y, Wang F, Wan K, Yamane K, Zhang Y, Lei M (2006) Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci USA 103:13956–13961PubMedGoogle Scholar
  68. 68.
    Stavropoulos P, Blobel G, Hoelz A (2006) Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol 13:626–632PubMedGoogle Scholar
  69. 69.
    Yang M, Gocke CB, Luo X, Borek D, Tomchick DR, Machius M, Otwinowski Z, Yu H (2006) Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol Cell 23:377–387PubMedGoogle Scholar
  70. 70.
    Yang M, Culhane JC, Szewczuk LM, Gocke CB, Brautigam CA, Tomchick DR, Machius M, Cole PA, Yu H (2007) Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nat Struct Mol Biol 14:535–539PubMedGoogle Scholar
  71. 71.
    Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A (2007) Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem 282:20070–20074PubMedGoogle Scholar
  72. 72.
    Trewick SC, McLaughlin PJ, Allshire RC (2005) Methylation: lost in hydroxylation? EMBO Rep 6:315–320PubMedGoogle Scholar
  73. 73.
    Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811–816PubMedGoogle Scholar
  74. 74.
    Falnes PO, Johansen RF, Seeberg E (2002) AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 419:178–182PubMedGoogle Scholar
  75. 75.
    Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B (2002) Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 419:174–178PubMedGoogle Scholar
  76. 76.
    Dann CE 3rd, Bruick RK (2005) Dioxygenases as O2-dependent regulators of the hypoxic response pathway. Biochem Biophys Res Commun 338:639–647PubMedGoogle Scholar
  77. 77.
    Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C, Butler DS, Yates JR 3rd, Delahunty CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ, Schofield CJ, Bottger A (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325:90–93PubMedGoogle Scholar
  78. 78.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by the MLL fusion partner TET1. Science 324(5929):930–935PubMedGoogle Scholar
  79. 79.
    Hoffart LM, Barr EW, Guyer RB, Bollinger JM Jr, Krebs C (2006) Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase. Proc Natl Acad Sci USA 103:14738–14743PubMedGoogle Scholar
  80. 80.
    Ozer A, Bruick RK (2007) Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? Nat Chem Biol 3:144–153PubMedGoogle Scholar
  81. 81.
    Tu S, Teng YC, Yuan C, Wu YT, Chan MY, Cheng AN, Lin PH, Juan LJ, Tsai MD (2008) The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif. Nat Struct Mol Biol 15:419–421PubMedGoogle Scholar
  82. 82.
    Chen Z, Zang J, Whetstine J, Hong X, Davrazou F, Kutateladze TG, Simpson M, Mao Q, Pan CH, Dai S, Hagman J, Hansen K, Shi Y, Zhang G (2006) Structural insights into histone demethylation by JMJD2 family members. Cell 125:691–702PubMedGoogle Scholar
  83. 83.
    Chen Z, Zang J, Kappler J, Hong X, Crawford F, Wang Q, Lan F, Jiang C, Whetstine J, Dai S, Hansen K, Shi Y, Zhang G (2007) Structural basis of the recognition of a methylated histone tail by JMJD2A. Proc Natl Acad Sci USA 104:10818–10823PubMedGoogle Scholar
  84. 84.
    Couture JF, Collazo E, Ortiz-Tello PA, Brunzelle JS, Trievel RC (2007) Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Mol Biol 14:689–695PubMedGoogle Scholar
  85. 85.
    Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BM, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer J, Scheinost JC, Borowski T, Sundstrom M, Schofield CJ, Oppermann U (2007) Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 448:87–91PubMedGoogle Scholar
  86. 86.
    Han Z, Liu P, Gu L, Zhang Y, Li H, Chen S, Chai J (2007) Structural basis for histone demethylation by JHDM1. Frontier Sci 1:52–67Google Scholar
  87. 87.
    Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM (2006) Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312:748–751PubMedGoogle Scholar
  88. 88.
    Lee J, Thompson JR, Botuyan MV, Mer G (2008) Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor. Nat Struct Mol Biol 15:109–111PubMedGoogle Scholar
  89. 89.
    Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ (2010) PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N{varepsilon}-dimethyl lysine demethylase. Hum Mol Genet 19:217–222Google Scholar
  90. 90.
    Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, Cheng X (2010) Enzymatic and structural insights for substrate specificity of a family of Jumonji histone lysine demethylases. Nat Struct Mol Biol 17:38–43Google Scholar
  91. 91.
    Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, Zhang Y (2006) JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125:483–495PubMedGoogle Scholar
  92. 92.
    Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128:1077–1088PubMedGoogle Scholar
  93. 93.
    Li F, Huarte M, Zaratiegui M, Vaughn MW, Shi Y, Martienssen R, Cande WZ (2008) Lid2 is required for coordinating H3K4 and H3K9 methylation of heterochromatin and euchromatin. Cell 135:272–283PubMedGoogle Scholar
  94. 94.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedGoogle Scholar
  95. 95.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedGoogle Scholar
  96. 96.
    Turner BM (2007) Defining an epigenetic code. Nat Cell Biol 9:2–6PubMedGoogle Scholar
  97. 97.
    Suganuma T, Workman JL (2008) Crosstalk among histone modifications. Cell 135:604–607PubMedGoogle Scholar
  98. 98.
    Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412PubMedGoogle Scholar
  99. 99.
    Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, Gnirke A, Jaenisch R, Lander ES (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770PubMedGoogle Scholar
  100. 100.
    Zhang Y, Rohde C, Tierling S, Jurkowski TP, Bock C, Santacruz D, Ragozin S, Reinhardt R, Groth M, Walter J, Jeltsch A (2009) DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution. PLoS Genet 5:e1000438PubMedGoogle Scholar
  101. 101.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322PubMedGoogle Scholar
  102. 102.
    Southall SM, Wong PS, Odho Z, Roe SM, Wilson JR (2009) Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. Mol Cell 33:181–191PubMedGoogle Scholar
  103. 103.
    Couture JF, Collazo E, Brunzelle JS, Trievel RC (2005) Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev 19:1455–1465PubMedGoogle Scholar
  104. 104.
    Xiao B, Jing C, Kelly G, Walker PA, Muskett FW, Frenkiel TA, Martin SR, Sarma K, Reinberg D, Gamblin SJ, Wilson JR (2005) Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes Dev 19:1444–1454PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Anup K. Upadhyay
    • 1
  • Xiaodong Cheng
    • 1
  1. 1.Department of BiochemistryEmory University School of MedicineAtlantaUSA

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