Molecular Neurobiology

, Volume 47, Issue 2, pp 740–756 | Cite as

Histone Methylation in the Nervous System: Functions and Dysfunctions



Chromatin remodeling is a key epigenetic process controlling the regulation of gene transcription. Local changes of chromatin architecture can be achieved by post-translational modifications of histones such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These changes are dynamic and allow for rapid repression or de-repression of specific target genes. Chromatin remodeling enzymes are largely involved in the control of cellular differentiation, and loss or gain of function is often correlated with pathological events. For these reasons, research on chromatin remodeling enzymes is currently very active and rapidly expanding, these enzymes representing very promising targets for the design of novel therapeutics in different areas of medicine including oncology and neurology. In this review, we focus on histone methylation in the nervous system. We provide an overview on mammalian histone methyltransferases and demethylases and their mechanisms of action, and we discuss their roles in the development of the nervous system and their involvement in neurodevelopmental, neurodegenerative, and behavioral disorders.


Chromatin remodeling Histone methylation Nervous system Development Differentiation Disease 



This work is supported by the Swiss National Science Foundation.

Conflicts of interest

The authors declare that they have no conflict of interest.


  1. 1.
    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 119:941–953PubMedCrossRefGoogle Scholar
  2. 2.
    Mosammaparast N, Shi Y (2010) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 79:155–179PubMedCrossRefGoogle Scholar
  3. 3.
    Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13:343–357PubMedCrossRefGoogle Scholar
  4. 4.
    Han S, Brunet A (2012) Histone methylation makes its mark on longevity. Trends Cell Biol 22:42–49PubMedCrossRefGoogle Scholar
  5. 5.
    Jacob C, Christen CN, Pereira JA, Somandin C, Baggiolini A, Lötscher P, Ozçelik M, Tricaud N, Meijer D, Yamaguchi T, Matthias P, Suter U (2011) HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells. Nat Neurosci 14:429–436PubMedCrossRefGoogle Scholar
  6. 6.
    Jacob C, Lebrun-Julien F, Suter U (2011) How histone deacetylases control myelination. Mol Neurobiol 44:303–312PubMedCrossRefGoogle Scholar
  7. 7.
    Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A, Livesey FJ (2010) Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A 107:15957–15962PubMedCrossRefGoogle Scholar
  8. 8.
    Sher F, Rossler R, Brouwer N, Balasubramaniyan V, Boddeke E, Copray S (2008) Differentiation of neural stem cells into oligodendrocytes: involvement of the polycomb group protein Ezh2. Stem Cells 26:2875–2883PubMedCrossRefGoogle Scholar
  9. 9.
    Al-Mahdawi S, Pinto RM, Ismail O, Varshney D, Lymperi S, Sandi C, Trabzuni D, Pook M (2008) The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet 17:735–746PubMedCrossRefGoogle Scholar
  10. 10.
    Xu J, Andreassi M (2011) Reversible histone methylation regulates brain gene expression and behavior. Horm Behav 59:383–392PubMedCrossRefGoogle Scholar
  11. 11.
    Murray K (1964) The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3:10–15PubMedCrossRefGoogle Scholar
  12. 12.
    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 406:593–599PubMedCrossRefGoogle Scholar
  13. 13.
    Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (2002) Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12:1052–1058PubMedCrossRefGoogle Scholar
  14. 14.
    Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395PubMedCrossRefGoogle Scholar
  15. 15.
    Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318:444–447PubMedCrossRefGoogle Scholar
  16. 16.
    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 325:90–93PubMedCrossRefGoogle Scholar
  17. 17.
    Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283PubMedCrossRefGoogle Scholar
  18. 18.
    Trievel RC (2004) Structure and function of histone methyltransferases. Crit Rev Eukaryot Gene Expr 14:147–169PubMedCrossRefGoogle Scholar
  19. 19.
    van Leeuwen F, Gafken PR, Gottschling DE (2002) Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109:745–756PubMedCrossRefGoogle Scholar
  20. 20.
    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 112:711–723PubMedCrossRefGoogle Scholar
  21. 21.
    McBride AE, Silver PA (2001) State of the Arg: protein methylation at arginine comes of age. Cell 106:5–8PubMedCrossRefGoogle Scholar
  22. 22.
    Wood A, Shilatifard A (2004) Posttranslational modifications of histones by methylation. Adv Protein Chem 67:201–222PubMedCrossRefGoogle Scholar
  23. 23.
    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 U S A 103:13956–13961PubMedCrossRefGoogle Scholar
  24. 24.
    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 439:811–816PubMedCrossRefGoogle Scholar
  25. 25.
    Tian XQ, Fang JY (2007) Current perspectives on histone demethylases. Acta Biochim Biophys Sin 39:81–88PubMedCrossRefGoogle Scholar
  26. 26.
    Cheung P, Lau P (2005) Epigenetic regulation by histone methylation and histone variants. Mol Endocrinol 19:563–573PubMedCrossRefGoogle Scholar
  27. 27.
    Krauss V (2008) Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its marks behind. Genetica 133:93–106PubMedCrossRefGoogle Scholar
  28. 28.
    Hublitz P, Albert M, Peters AH (2009) Mechanisms of transcriptional repression by histone lysine methylation. Int J Dev Biol 53:335–354PubMedCrossRefGoogle Scholar
  29. 29.
    Bernstein BE, Humphrey EL, Erlich RL, Schneider R, Bouman P, Liu JS, Kouzarides T, Schreiber SL (2002) Methylation of histone H3 Lys 4 in coding regions of active genes. Proc Natl Acad Sci U S A 99:8695–8700PubMedCrossRefGoogle Scholar
  30. 30.
    Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NCT, Schreiber SL, Mellor J, Kouzarides T (2002) Active genes are tri-methylated at K4 of histone H3. Nature 419:407–411PubMedCrossRefGoogle Scholar
  31. 31.
    Wagner EJ, Carpenter PB (2012) Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol 13:115–126PubMedCrossRefGoogle Scholar
  32. 32.
    Nguyen AT, Zhang Y (2011) The diverse functions of Dot1 and H3K79 methylation. Genes Dev 25:1345–1358PubMedCrossRefGoogle Scholar
  33. 33.
    Di Lorenzo A, Bedford MT (2011) Histone arginine methylation. FEBS Lett 585:2024–2031PubMedCrossRefGoogle Scholar
  34. 34.
    Fritsch C, Brown JL, Kassis JA, Muller J (1999) The DNA-binding polycomb group protein pleiohomeotic mediates silencing of a drosophila homeotic gene. Development 126:3905–3913PubMedGoogle Scholar
  35. 35.
    Tillib S, Petruk S, Sedkov Y, Kuzin A, Fujioka M, Goto T, Mazo A (1999) Trithorax- and polycomb-group response elements within an ultrabithorax transcription maintenance unit consist of closely situated but separable sequences. Mol Cell Biol 19:5189–5202PubMedGoogle Scholar
  36. 36.
    Woo CJ, Kharchenko PV, Daheron L, Park PJ, Kingston RE (2010) A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 140:99–110PubMedCrossRefGoogle Scholar
  37. 37.
    Pasini D, Cloos PAC, Walfridsson J, Olsson L, Bukowski JP, Johansen JV, Bak M, Tommerup N, Rappsilber J, Helin K (2010) JARID2 regulates binding of the polycomb repressive complex 2 to target genes in ES cells. Nature 464:306–310PubMedCrossRefGoogle Scholar
  38. 38.
    Walker E, Chang WY, Hunkapiller J, Cagney G, Garcha K, Torchia J, Krogan NJ, Reiter JF, Stanford WL (2010) Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell 6:153–166PubMedCrossRefGoogle Scholar
  39. 39.
    Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Genes Dev 16:2893–2905PubMedCrossRefGoogle Scholar
  40. 40.
    Hawkins PG, Morris KV (2010) Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription 1:165–175PubMedCrossRefGoogle Scholar
  41. 41.
    Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329:689–693PubMedCrossRefGoogle Scholar
  42. 42.
    Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472:120–124PubMedCrossRefGoogle Scholar
  43. 43.
    Fukagawa T, Nogami M, Yoshikawa M, Ikeno M, Okazaki T, Takami Y, Nakayama T, Oshimura M (2004) Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nat Cell Biol 6:784–791PubMedCrossRefGoogle Scholar
  44. 44.
    Ogawa Y, Sun BK, Lee JT (2008) Intersection of the RNA interference and X-inactivation pathways. Science 320:1336–1341PubMedCrossRefGoogle Scholar
  45. 45.
    van Wolfswinkel JC, Ketting RF (2010) The role of small non-coding RNAs in genome stability and chromatin organization. J Cell Sci 123:1825–1839PubMedCrossRefGoogle Scholar
  46. 46.
    Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T (2010) Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143:470–484PubMedCrossRefGoogle Scholar
  47. 47.
    Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V, Brunzelle J, Couture JF (2011) Structural and biochemical insights into MLL1 core complex assembly. Structure 19:101–108PubMedCrossRefGoogle Scholar
  48. 48.
    Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL, Roeder RG (2005) Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121:873–885PubMedCrossRefGoogle Scholar
  49. 49.
    Paggetti J, Largeot A, Aucagne R, Jacquel A, Lagrange B, Yang XJ, Solary E, Bastie JN, Delva L (2010) Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34 + cells. Oncogene 29:5019–5031PubMedCrossRefGoogle Scholar
  50. 50.
    Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10:1107–1117PubMedCrossRefGoogle Scholar
  51. 51.
    Wysocka J, Myers MP, Laherty CD, Eisenman RN, Herr W (2003) Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17:896–911PubMedCrossRefGoogle Scholar
  52. 52.
    Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, Herr W, Cleary ML (2004) Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol 24:5639–5649PubMedCrossRefGoogle Scholar
  53. 53.
    Slany RK (2005) Chromatin control of gene expression: mixed-lineage leukemia methyltransferase SETs the stage for transcription. Proc Natl Acad Sci U S A 102:14481–14482PubMedCrossRefGoogle Scholar
  54. 54.
    Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd (2002) SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 16:919–932PubMedCrossRefGoogle Scholar
  55. 55.
    Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002) Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21:148–152PubMedCrossRefGoogle Scholar
  56. 56.
    Vaute O, Nicolas E, Vandel L, Trouche D (2002) Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases. Nucleic Acids Res 30:475–481PubMedCrossRefGoogle Scholar
  57. 57.
    Liu DX, Nath N, Chellappan SP, Greene LA (2005) Regulation of neuron survival and death by p130 and associated chromatin modifiers. Genes Dev 19:719–732PubMedCrossRefGoogle Scholar
  58. 58.
    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 16:1779–1791PubMedCrossRefGoogle Scholar
  59. 59.
    Hiragami K, Festenstein R (2005) Heterochromatin protein 1: a pervasive controlling influence. Cell Mol Life Sci 62:2711–2726PubMedCrossRefGoogle Scholar
  60. 60.
    Smallwood A, Esteve PO, Pradhan S, Carey M (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev 21:1169–1178PubMedCrossRefGoogle Scholar
  61. 61.
    Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y (2002) Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298:1039–1043PubMedCrossRefGoogle Scholar
  62. 62.
    Margueron R, Reinberg D (2011) The polycomb complex PRC2 and its mark in life. Nature 469:343–349PubMedCrossRefGoogle Scholar
  63. 63.
    Endoh M, Endo TA, Endoh T, Isono K, Sharif J, Ohara O, Toyoda T, Ito T, Eskeland R, Bickmore WA, Vidal M, Bernstein BE, Koseki H (2012) Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. PLoS Genet 8:e1002774PubMedCrossRefGoogle Scholar
  64. 64.
    Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D (2008) Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 32:503–518PubMedCrossRefGoogle Scholar
  65. 65.
    Xu C, Bian C, Yang W, Galka M, Ouyang H, Chen C, Qiu W, Liu H, Jones AE, MacKenzie F, Pan P, Li SS, Wang H, Min J (2010) Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2). Proc Natl Acad Sci U S A 107:19266–19271PubMedCrossRefGoogle Scholar
  66. 66.
    Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ 3rd, 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 461:762–767PubMedCrossRefGoogle Scholar
  67. 67.
    Cao R, Zhang Y (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 15:57–67PubMedCrossRefGoogle Scholar
  68. 68.
    Pasini D, Bracken AP, Jensen MR, Denchi EL, Helin K (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–4071PubMedCrossRefGoogle Scholar
  69. 69.
    Kim H, Kang K, Kim J (2009) AEBP2 as a potential targeting protein for polycomb repression complex PRC2. Nucleic Acids Res 37:2940–2950PubMedCrossRefGoogle Scholar
  70. 70.
    Peng JC, Valouev A, Swigut T, Zhang J, Zhao Y, Sidow A, Wysocka J (2009) Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139:1290–1302PubMedCrossRefGoogle Scholar
  71. 71.
    Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D (2008) Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol 28:2718–2731PubMedCrossRefGoogle Scholar
  72. 72.
    Walker E, Manias JL, Chang WY, Stanford WL (2011) PCL2 modulates gene regulatory networks controlling self-renewal and commitment in embryonic stem cells. Cell Cycle 10:45–51Google Scholar
  73. 73.
    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 19:857–864PubMedCrossRefGoogle Scholar
  74. 74.
    Shi Y, Sawada J, Sui G, el Affar B, Whetstine JR, Lan F, Ogawa H, Luke MP, Nakatani Y, Shi Y (2003) Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422:735–738PubMedCrossRefGoogle Scholar
  75. 75.
    Wang Y, Zhang H, Chen YP, Sun YM, Yang F, Yu WH, Liang J, Sun LY, Yang XH, Shi L, Li RF, Li YY, Zhang Y, Li Q, Yi X, Shang YF (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138:660–672PubMedCrossRefGoogle Scholar
  76. 76.
    Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A, Shi Y (2007) The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 447:601–605PubMedCrossRefGoogle Scholar
  77. 77.
    Zhang DZ, Yoon HG, Wong JM (2005) 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 25:6404–6414PubMedCrossRefGoogle Scholar
  78. 78.
    Hayakawa T, Ohtani Y, Hayakawa N, Shinmyozu K, Saito M, Ishikawa F, Nakayama J (2007) RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylation. Genes Cells 12:811–826PubMedGoogle Scholar
  79. 79.
    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
  80. 80.
    Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, Ju BG, Ohgi KA, Wang J, Escoubet-Lozach L, Rose DW, Glass CK, Fu XD, Rosenfeld MG (2007) Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128:505–518PubMedCrossRefGoogle Scholar
  81. 81.
    Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK, Hermanson O, Rosenfeld MG (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450:415–419PubMedCrossRefGoogle Scholar
  82. 82.
    Burgold T, Spreafico F, De Santa F, Totaro MG, Prosperini E, Natoli G, Testa G (2008) The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PLoS One 3:e3034PubMedCrossRefGoogle Scholar
  83. 83.
    Estaras C, Akizu N, Garcia A, Beltran S, de la Cruz X, Martinez-Balbas MA (2012) Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development 139:2681–2691PubMedCrossRefGoogle Scholar
  84. 84.
    Lim DA, Huang YC, Swigut T, Mirick AL, Garcia-Verdugo JM, Wysocka J, Ernst P, Alvarez-Buylla A (2009) Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458:529–533PubMedCrossRefGoogle Scholar
  85. 85.
    Patel SR, Kim D, Levitan I, Dressler GR (2007) The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell 13:580–592PubMedCrossRefGoogle Scholar
  86. 86.
    Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G (2005) REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121:645–657PubMedCrossRefGoogle Scholar
  87. 87.
    Abrajano JJ, Qureshi IA, Gokhan S, Zheng DY, Bergman A, Mehler MF (2009) REST and CoREST modulate neuronal subtype specification, maturation and maintenance. PLoS One 4:e7936PubMedCrossRefGoogle Scholar
  88. 88.
    Sen N, Snyder SH (2011) Neurotrophin-mediated degradation of histone methyltransferase by S-nitrosylation cascade regulates neuronal differentiation. Proc Natl Acad Sci U S A 108:20178–20183PubMedCrossRefGoogle Scholar
  89. 89.
    Asensio-Juan E, Gallego C, Martinez-Balbas MA (2012) The histone demethylase PHF8 is essential for cytoskeleton dynamics. Nucleic Acids Res 40:9429–9440PubMedCrossRefGoogle Scholar
  90. 90.
    Tan SL, Nishi M, Ohtsuka T, Matsui T, Takemoto K, Kamio-Miura A, Aburatani H, Shinkai Y, Kageyama R (2012) Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. Development 139:3806–3816PubMedCrossRefGoogle Scholar
  91. 91.
    Weng MK, Zimmer B, Poltl D, Broeg MP, Ivanova V, Gaspar JA, Sachinidis A, Wullner U, Waldmann T, Leist M (2012) Extensive transcriptional regulation of chromatin modifiers during human neurodevelopment. PLoS One 7:e36708PubMedCrossRefGoogle Scholar
  92. 92.
    Sher F, Boddeke E, Olah M, Copray S (2012) Dynamic changes in Ezh2 gene occupancy underlie its involvement in neural stem cell self-renewal and differentiation towards oligodendrocytes. PLoS One 7:e40399PubMedCrossRefGoogle Scholar
  93. 93.
    Shen S, Li J, Casaccia-Bonnefil P (2005) Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J Cell Biol 169:577–589PubMedCrossRefGoogle Scholar
  94. 94.
    Abrajano JJ, Qureshi IA, Gokhan S, Zheng D, Bergman A, Mehler MF (2009) Differential deployment of REST and CoREST promotes glial subtype specification and oligodendrocyte lineage maturation. PLoS One 4:e7665PubMedCrossRefGoogle Scholar
  95. 95.
    Heinen A, Tzekova N, Graffmann N, Torres KJ, Uhrberg M, Hartung HP, Kury P (2012) Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation. Glia 60:1696–1708PubMedCrossRefGoogle Scholar
  96. 96.
    Heinen A, Kremer D, Gottle P, Kruse F, Hasse B, Lehmann H, Hartung HP, Kury P (2008) The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination. Proc Natl Acad Sci U S A 105:8748–8753PubMedCrossRefGoogle Scholar
  97. 97.
    Song MR, Ghosh A (2004) FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat Neurosci 7:229–235PubMedCrossRefGoogle Scholar
  98. 98.
    Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE (2006) Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis 193:963–970PubMedCrossRefGoogle Scholar
  99. 99.
    Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C, Aunis D, Rohr O (2007) Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 26:412–423PubMedCrossRefGoogle Scholar
  100. 100.
    Cherrier T, Suzanne S, Redel L, Calao M, Marban C, Samah B, Mukerjee R, Schwartz C, Gras G, Sawaya BE, Zeichner SL, Aunis D, Van Lint C, Rohr O (2009) p21(WAF1) gene promoter is epigenetically silenced by CTIP2 and SUV39H1. Oncogene 28:3380–3389PubMedCrossRefGoogle Scholar
  101. 101.
    Le Douce V, Colin L, Redel L, Cherrier T, Herbein G, Aunis D, Rohr O, Van Lint C, Schwartz C (2012) LSD1 cooperates with CTIP2 to promote HIV-1 transcriptional silencing. Nucleic Acids Res 40:1904–1915PubMedCrossRefGoogle Scholar
  102. 102.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59PubMedCrossRefGoogle Scholar
  103. 103.
    Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, Janecke AR, Tariverdian G, Chelly J, Fryns JP, Van Esch H, Kleefstra T, Hamel B, Moraine C, Gecz J, Turner G, Reinhardt R, Kalscheuer VM, Ropers HH, Lenzner S (2005) Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet 76:227–236PubMedCrossRefGoogle Scholar
  104. 104.
    Santos C, Rodriguez-Revenga L, Madrigal I, Badenas C, Pineda M, Mila M (2006) A novel mutation in JARID1C gene associated with mental retardation. Eur J Hum Genet 14:583–586PubMedCrossRefGoogle Scholar
  105. 105.
    Tzschach A, Lenzner S, Moser B, Reinhardt R, Chelly J, Fryns JP, Kleefstra T, Raynaud M, Turner G, Ropers HH, Kuss A, Jensen LR (2006) Novel JARID1C/SMCX mutations in patients with X-linked mental retardation. Hum Mutat 27:389PubMedCrossRefGoogle Scholar
  106. 106.
    Adegbola A, Gao H, Sommer S, Browning M (2008) A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). Am J Med Genet A 146A:505–511PubMedCrossRefGoogle Scholar
  107. 107.
    Santos-Reboucas CB, Fintelman-Rodrigues N, Jensen LR, Kuss AW, Ribeiro MG, Campos M Jr, Santos JM, Pimentel MM (2011) A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neurosci Lett 498:67–71PubMedCrossRefGoogle Scholar
  108. 108.
    Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C, Phan-Dinh Tuy F, van Bokhoven H, Fryns JP, Chelly J, Ropers HH, Moraine C, Hamel BC, Briault S (2005) Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet 42:780–786PubMedCrossRefGoogle Scholar
  109. 109.
    Koivisto AM, Ala-Mello S, Lemmela S, Komu HA, Rautio J, Jarvela I (2007) Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin Genet 72:145–149PubMedCrossRefGoogle Scholar
  110. 110.
    Abidi FE, Miano MG, Murray JC, Schwartz CE (2007) A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet 72:19–22PubMedCrossRefGoogle Scholar
  111. 111.
    Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H (2006) Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79:370–377PubMedCrossRefGoogle Scholar
  112. 112.
    Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier KA, Smith KM, Ferrante RJ (2006) ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington’s disease. Proc Natl Acad Sci U S A 103:19176–19181PubMedCrossRefGoogle Scholar
  113. 113.
    Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW, van den Hove DL (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90:498–510PubMedCrossRefGoogle Scholar
  114. 114.
    Lithner C, Hernandez C, Nordberg A, Sweatt D (2009) Epigenetic changes related to beta-amyloid—implications for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 5:P304CrossRefGoogle Scholar
  115. 115.
    Shen SM, Liu AX, Li JD, Wolubah C, Casaccia-Bonnefil P (2008) Epigenetic memory loss in aging oligodendrocytes in the corpus callosum. Neurobiol Aging 29:452–463PubMedCrossRefGoogle Scholar
  116. 116.
    Shen SM, Sandoval J, Swiss VA, Li JD, Dupree J, Franklin RJM, Casaccia-Bonnefil P (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11:1024–1034PubMedCrossRefGoogle Scholar
  117. 117.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525PubMedCrossRefGoogle Scholar
  118. 118.
    Kuzumaki N, Ikegami D, Tamura R, Hareyama N, Imai S, Narita M, Torigoe K, Niikura K, Takeshima H, Ando T, Igarashi K, Kanno J, Ushijima T, Suzuki T, Narita M (2011) Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment. Hippocampus 21:127–132PubMedCrossRefGoogle Scholar
  119. 119.
    Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D, Kodadek TJ, Nestler EJ (2009) Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J Neurosci 29:7820–7832PubMedCrossRefGoogle Scholar
  120. 120.
    Jiang Y, Jakovcevski M, Bharadwaj R, Connor C, Schroeder FA, Lin CL, Straubhaar J, Martin G, Akbarian S (2010) Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B. J Neurosci 30:7152–7167PubMedCrossRefGoogle Scholar
  121. 121.
    Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor RE, Lubin FD (2010) Histone methylation regulates memory formation. J Neurosci 30:3589–3599PubMedCrossRefGoogle Scholar
  122. 122.
    Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S (2007) Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 27:11254–11262PubMedCrossRefGoogle Scholar
  123. 123.
    Maze I, Covington HE 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216PubMedCrossRefGoogle Scholar
  124. 124.
    Covington HE 3rd, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, Dietz DM, Lobo MK, Ghose S, Mouzon E, Neve RL, Tamminga CA, Nestler EJ (2011) A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 71:656–670PubMedCrossRefGoogle Scholar
  125. 125.
    Xu J, Deng X, Disteche CM (2008) Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PLoS One 3:e2553PubMedCrossRefGoogle Scholar
  126. 126.
    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 128:1077–1088PubMedCrossRefGoogle Scholar
  127. 127.
    Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y (2010) Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 466:503–507PubMedCrossRefGoogle Scholar
  128. 128.
    Balemans MC, Huibers MM, Eikelenboom NW, Kuipers AJ, van Summeren RC, Pijpers MM, Tachibana M, Shinkai Y, van Bokhoven H, Van der Zee CE (2010) Reduced exploration, increased anxiety, and altered social behavior: autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behav Brain Res 208:47–55PubMedCrossRefGoogle Scholar
  129. 129.
    Fritsch L, Robin P, Mathieu JRR, Souidi M, Hinaux H, Rougeulle C, Harel-Bellan A, Ameyar-Zazoua M, Ait-Si-Ali S (2010) A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell 37:46–56PubMedCrossRefGoogle Scholar
  130. 130.
    Schaefer A, Sampath SC, Intrator A, Min A, Gertler TS, Surmeier DJ, Tarakhovsky A, Greengard P (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64:678–691PubMedCrossRefGoogle Scholar
  131. 131.
    Schmucker S, Puccio H (2010) Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches. Hum Mol Genet 19:R103–R110PubMedCrossRefGoogle Scholar
  132. 132.
    Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22:1277–1287PubMedCrossRefGoogle Scholar
  133. 133.
    Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N, Krainc D (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296:2238–2243PubMedCrossRefGoogle Scholar
  134. 134.
    Yu ZX, Li SH, Nguyen HP, Li XJ (2002) Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice. Hum Mol Genet 11:905–914PubMedCrossRefGoogle Scholar
  135. 135.
    Williams TL, Serpell LC (2011) Membrane and surface interactions of Alzheimer’s Aβ peptide-insights into the mechanism of cytotoxicity. FEBS J 278:3905–3917PubMedCrossRefGoogle Scholar
  136. 136.
    Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127PubMedCrossRefGoogle Scholar
  137. 137.
    Hunter RG, McCarthy KJ, Milne TA, Pfaff DW, McEwen BS (2009) Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci U S A 106:20912–20917PubMedCrossRefGoogle Scholar
  138. 138.
    Mashayekhi FJ, Rasti M, Rahvar M, Mokarram P, Namavar MR, Owji AA (2012) Expression levels of the BDNF gene and histone modifications around its promoters in the ventral tegmental area and locus ceruleus of rats during forced abstinence from morphine. Neurochem Res 37:1517–1523PubMedCrossRefGoogle Scholar
  139. 139.
    Jakovcevski M, Akbarian S (2012) Epigenetic mechanisms in neurological disease. Nat Med 18:1194–1204PubMedCrossRefGoogle Scholar
  140. 140.
    Kelly TK, De Carvalho DD, Jones PA (2010) Epigenetic modifications as therapeutic targets. Nat Biotechnol 28:1069–1078PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Biology, Unit of ZoologyUniversity of FribourgFribourgSwitzerland

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