Histone and DNA Modifications in Mental Retardation

Part of the Progress in Drug Research book series (PDR, volume 67)


Mental retardation (MR), which affects 1–3% of the total population, refers to a pathological condition whereby the affected individuals suffer from cognitive impairment, which is diagnosed by a low intelligence quotient (IQ) (<70). Over the years, human genetic studies identified a plethora of candidate genes causing MR, but mechanisms by which these candidates regulate cognitive function remain poorly understood. While the functions of MR genes range from cell signaling and gene expression to synaptic plasticity, there is growing evidence supporting a critical role for epigenetic and chromatin regulatory proteins in MR. Excitingly, recent molecular and genetic studies suggest the possibility of improving cognitive functions via modulation of epigenetic regulators, highlighting a potentially new avenue for therapeutic intervention. In this review, we discuss recent studies on epigenetic regulation in MR and explore the concept of epigenetic therapy for MR.


Mental Retardation Rett Syndrome Postmitotic Neuron Charge Syndrome Histone Modify Enzyme 
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.


  1. 1.
    Inlow JK, Restifo LL (2004) Molecular and comparative genetics of mental retardation. Genetics 166:835–881PubMedCrossRefGoogle Scholar
  2. 2.
    Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O’Meara S, Latimer C, Dicks E, Menzies A et al (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41:535–543PubMedCrossRefGoogle Scholar
  3. 3.
    Ropers HH, Hamel BC (2005) X-linked mental retardation. Nat Rev Genet 6:46–57PubMedCrossRefGoogle Scholar
  4. 4.
    Chiurazzi P, Schwartz CE, Gecz J, Neri G (2008) XLMR genes: update 2007. Eur J Hum Genet 16:422–434PubMedCrossRefGoogle Scholar
  5. 5.
    Akbarian S, Huang HS (2009) Epigenetic regulation in human brain-focus on histone lysine methylation. Biol Psychiatry 65:198–203PubMedCrossRefGoogle Scholar
  6. 6.
    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21PubMedCrossRefGoogle Scholar
  7. 7.
    Ooi SK, O’Donnell AH, Bestor TH (2009) Mammalian cytosine methylation at a glance. J Cell Sci 122:2787–2791PubMedCrossRefGoogle Scholar
  8. 8.
    Illingworth RS, Bird AP (2009) CpG islands – ‘a rough guide’. FEBS Lett 583:1713–1720PubMedCrossRefGoogle Scholar
  9. 9.
    Ono T, Uehara Y, Kurishita A, Tawa R, Sakurai H (1993) Biological significance of DNA methylation in the ageing process. Age Ageing 22:S34–S43PubMedCrossRefGoogle Scholar
  10. 10.
    Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951PubMedGoogle Scholar
  11. 11.
    Tawa R, Ono T, Kurishita A, Okada S, Hirose S (1990) Changes of DNA methylation level during pre- and postnatal periods in mice. Differentiation 45:44–48PubMedCrossRefGoogle Scholar
  12. 12.
    Ballestar E, Wolffe AP (2001) Methyl-CpG-binding proteins. Targeting specific gene repression. Eur J Biochem 268:1–6PubMedCrossRefGoogle Scholar
  13. 13.
    Wade PA (2001) Methyl CpG-binding proteins and transcriptional repression. Bioessays 23:1131–1137PubMedCrossRefGoogle Scholar
  14. 14.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedCrossRefGoogle Scholar
  15. 15.
    Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96:14412–14417PubMedCrossRefGoogle Scholar
  16. 16.
    Ehrlich M (2003) The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 109:17–28PubMedCrossRefGoogle Scholar
  17. 17.
    Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J et al (2008) DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 17:690–709PubMedCrossRefGoogle Scholar
  18. 18.
    Fan G, Beard C, Chen RZ, Csankovszki G, Sun Y, Siniaia M, Biniszkiewicz D, Bates B, Lee PP, Kuhn R et al (2001) DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 21:788–797PubMedGoogle Scholar
  19. 19.
    Zhu JK (2009) Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet 43:143–166PubMedCrossRefGoogle Scholar
  20. 20.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedCrossRefGoogle Scholar
  21. 21.
    Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–930PubMedCrossRefGoogle Scholar
  22. 22.
    Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302:885–889PubMedCrossRefGoogle Scholar
  23. 23.
    Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893PubMedCrossRefGoogle Scholar
  24. 24.
    Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869PubMedCrossRefGoogle Scholar
  25. 25.
    Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29:12764–12767PubMedCrossRefGoogle Scholar
  26. 26.
    Greer PL, Greenberg ME (2008) From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59:846–860PubMedCrossRefGoogle Scholar
  27. 27.
    Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135:1201–1212PubMedCrossRefGoogle Scholar
  28. 28.
    Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, Flavell RA, Lu B, Ming GL, Song H (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077PubMedCrossRefGoogle Scholar
  29. 29.
    Rett A (1966) On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien Med Wochenschr 116:723–726PubMedGoogle Scholar
  30. 30.
    Armstrong D, Dunn JK, Antalffy B, Trivedi R (1995) Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol 54:195–201PubMedCrossRefGoogle Scholar
  31. 31.
    Belichenko PV, Hagberg B, Dahlstrom A (1997) Morphological study of neocortical areas in Rett syndrome. Acta Neuropathol 93:50–61PubMedCrossRefGoogle Scholar
  32. 32.
    Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326PubMedCrossRefGoogle Scholar
  33. 33.
    Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331PubMedCrossRefGoogle Scholar
  34. 34.
    Kishi N, Macklis JD (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 27:306–321PubMedCrossRefGoogle Scholar
  35. 35.
    Mullaney BC, Johnston MV, Blue ME (2004) Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain. Neuroscience 123:939–949PubMedCrossRefGoogle Scholar
  36. 36.
    Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY (2002) Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet 11:115–124PubMedCrossRefGoogle Scholar
  37. 37.
    Fukuda T, Itoh M, Ichikawa T, Washiyama K, Goto Y (2005) Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol 64:537–544PubMedGoogle Scholar
  38. 38.
    Matarazzo V, Cohen D, Palmer AM, Simpson PJ, Khokhar B, Pan SJ, Ronnett GV (2004) The transcriptional repressor Mecp2 regulates terminal neuronal differentiation. Mol Cell Neurosci 27:44–58PubMedCrossRefGoogle Scholar
  39. 39.
    Smrt RD, Eaves-Egenes J, Barkho BZ, Santistevan NJ, Zhao C, Aimone JB, Gage FH, Zhao X (2007) Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis 27:77–89PubMedCrossRefGoogle Scholar
  40. 40.
    Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM (2006) Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 21:217–227PubMedCrossRefGoogle Scholar
  41. 41.
    Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt JD, Zoghbi HY (2006) Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 26:319–327PubMedCrossRefGoogle Scholar
  42. 42.
    Nelson ED, Kavalali ET, Monteggia LM (2006) MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr Biol 16:710–716PubMedCrossRefGoogle Scholar
  43. 43.
    Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB (2005) Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 102:12560–12565PubMedCrossRefGoogle Scholar
  44. 44.
    Pelka GJ, Watson CM, Radziewic T, Hayward M, Lahooti H, Christodoulou J, Tam PP (2006) Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain 129:887–898PubMedCrossRefGoogle Scholar
  45. 45.
    Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci USA 104:1931–1936PubMedCrossRefGoogle Scholar
  46. 46.
    Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147PubMedCrossRefGoogle Scholar
  47. 47.
    Willard HF, Hendrich BD (1999) Breaking the silence in Rett syndrome. Nat Genet 23:127–128PubMedCrossRefGoogle Scholar
  48. 48.
    Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229PubMedCrossRefGoogle Scholar
  49. 49.
    Horike S, Cai S, Miyano M, Cheng JF, Kohwi-Shigematsu T (2005) Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 37:31–40PubMedCrossRefGoogle Scholar
  50. 50.
    Lalande M, Minassian BA, DeLorey TM, Olsen RW (1999) Parental imprinting and Angelman syndrome. Adv Neurol 79:421–429PubMedGoogle Scholar
  51. 51.
    Yasui DH, Peddada S, Bieda MC, Vallero RO, Hogart A, Nagarajan RP, Thatcher KN, Farnham PJ, Lasalle JM (2007) Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci USA 104:19416–19421PubMedCrossRefGoogle Scholar
  52. 52.
    Skene PJ, Illingworth RS, Webb S, Kerr AR, James KD, Turner DJ, Andrews R, Bird AP (2010) Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell 37:457–468PubMedCrossRefGoogle Scholar
  53. 53.
    Zhao X, Ueba T, Christie BR, Barkho B, McConnell MJ, Nakashima K, Lein ES, Eadie BD, Willhoite AR, Muotri AR et al (2003) Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc Natl Acad Sci USA 100:6777–6782PubMedCrossRefGoogle Scholar
  54. 54.
    Allfrey VG (1966) Structural modifications of histones and their possible role in the regulation of ribonucleic acid synthesis. Proc Can Cancer Conf 6:313–335Google Scholar
  55. 55.
    Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD (1996) Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84:843–851PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15:2343–2360PubMedCrossRefGoogle Scholar
  57. 57.
    Luger K, Richmond TJ (1998) The histone tails of the nucleosome. Curr Opin Genet Dev 8:140–146PubMedCrossRefGoogle Scholar
  58. 58.
    Edmondson DG, Smith MM, Roth SY (1996) Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes Dev 10:1247–1259PubMedCrossRefGoogle Scholar
  59. 59.
    Hecht A, Laroche T, Strahl-Bolsinger S, Gasser SM, Grunstein M (1995) Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80:583–592PubMedCrossRefGoogle Scholar
  60. 60.
    Bannister AJ, Kouzarides T (1996) The CBP co-activator is a histone acetyltransferase. Nature 384:641–643PubMedCrossRefGoogle Scholar
  61. 61.
    Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365:855–859PubMedCrossRefGoogle Scholar
  62. 62.
    Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445PubMedCrossRefGoogle Scholar
  63. 63.
    Pinsker HM, Hening WA, Carew TJ, Kandel ER (1973) Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science 182:1039–1042PubMedCrossRefGoogle Scholar
  64. 64.
    Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038PubMedCrossRefGoogle Scholar
  65. 65.
    Cohen S, Greenberg ME (2008) Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu Rev Cell Dev Biol 24:183–209PubMedCrossRefGoogle Scholar
  66. 66.
    Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ et al (1995) Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376:348–351PubMedCrossRefGoogle Scholar
  67. 67.
    Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004) Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42:947–959PubMedCrossRefGoogle Scholar
  68. 68.
    Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972PubMedCrossRefGoogle Scholar
  69. 69.
    Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411PubMedCrossRefGoogle Scholar
  70. 70.
    Grozinger CM, Schreiber SL (2002) Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 9:3–16PubMedCrossRefGoogle Scholar
  71. 71.
    Ayer DE (1999) Histone deacetylases: transcriptional repression with SINers and NuRDs. Trends Cell Biol 9:193–198PubMedCrossRefGoogle Scholar
  72. 72.
    Chinnadurai G (2002) CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol Cell 9:213–224PubMedCrossRefGoogle Scholar
  73. 73.
    Jones PL, Shi YB (2003) N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear hormone receptors. Curr Top Microbiol Immunol 274:237–268PubMedCrossRefGoogle Scholar
  74. 74.
    Hildmann C, Riester D, Schwienhorst A (2007) Histone deacetylases – an important class of cellular regulators with a variety of functions. Appl Microbiol Biotechnol 75:487–497PubMedCrossRefGoogle Scholar
  75. 75.
    Guan Z, Giustetto M, Lomvardas S, Kim JH, Miniaci MC, Schwartz JH, Thanos D, Kandel ER (2002) Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111:483–493PubMedCrossRefGoogle Scholar
  76. 76.
    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60PubMedCrossRefGoogle Scholar
  77. 77.
    Morrison AJ, Shen X (2005) DNA repair in the context of chromatin. Cell Cycle 4:568–571PubMedCrossRefGoogle Scholar
  78. 78.
    Altaf M, Saksouk N, Cote J (2007) Histone modifications in response to DNA damage. Mutat Res 618:81–90PubMedCrossRefGoogle Scholar
  79. 79.
    Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719PubMedCrossRefGoogle Scholar
  80. 80.
    Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318PubMedCrossRefGoogle Scholar
  81. 81.
    Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560PubMedCrossRefGoogle Scholar
  82. 82.
    Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation: dynamic or static? Cell 109:801–806PubMedCrossRefGoogle Scholar
  83. 83.
    Kubicek S, Jenuwein T (2004) A crack in histone lysine methylation. Cell 119:903–906PubMedCrossRefGoogle Scholar
  84. 84.
    Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103–1106PubMedCrossRefGoogle Scholar
  85. 85.
    Shi Y, Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25:1–14PubMedCrossRefGoogle Scholar
  86. 86.
    Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8:307–318PubMedCrossRefGoogle Scholar
  87. 87.
    Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y et al (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366PubMedCrossRefGoogle Scholar
  88. 88.
    Ellison J (2008) Gene symbol: NSD1. Disease: Sotos syndrome. Hum Genet 124:311PubMedGoogle Scholar
  89. 89.
    Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K, Song L, Lerouge T, Hager GL, Chambon P, Losson R (2003) NSD1 is essential for early post-implantation development and has a catalytically active SET domain. Embo J 22:3153–3163PubMedCrossRefGoogle Scholar
  90. 90.
    Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ 3rd, Qiao Q, Neubert TA, Xu RM, Gozani O et al (2009) The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284:34283–34295PubMedCrossRefGoogle Scholar
  91. 91.
    Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, Shia WJ, Anderson S, Yates J, Washburn MP et al (2005) Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123:581–592PubMedCrossRefGoogle Scholar
  92. 92.
    Joshi AA, Struhl K (2005) Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Mol Cell 20:971–978PubMedCrossRefGoogle Scholar
  93. 93.
    Keogh MC, Kurdistani SK, Morris SA, Ahn SH, Podolny V, Collins SR, Schuldiner M, Chin K, Punna T, Thompson NJ et al (2005) Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123:593–605PubMedCrossRefGoogle Scholar
  94. 94.
    Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Chambon P, Losson R (1998) Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. Embo J 17:3398–3412PubMedCrossRefGoogle Scholar
  95. 95.
    Bremner JD, McCaffery P (2008) The neurobiology of retinoic acid in affective disorders. Prog Neuropsychopharmacol Biol Psychiatry 32:315–331PubMedCrossRefGoogle Scholar
  96. 96.
    McCaffery P, Zhang J, Crandall JE (2006) Retinoic acid signaling and function in the adult hippocampus. J Neurobiol 66:780–791PubMedCrossRefGoogle Scholar
  97. 97.
    Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A et al (2009) Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 46:598–606PubMedCrossRefGoogle Scholar
  98. 98.
    Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y (2002) A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296:1132–1136PubMedCrossRefGoogle Scholar
  99. 99.
    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 19:815–826PubMedCrossRefGoogle Scholar
  100. 100.
    Stewart DR, Kleefstra T (2007) The chromosome 9q subtelomere deletion syndrome. Am J Med Genet C Semin Med Genet 145C:383–392PubMedCrossRefGoogle Scholar
  101. 101.
    Balemans MC, Huibers MM, Eikelenboom NW, Kuipers AJ, Summeren RC, Pijpers MM, Tachibana M, Shinkai Y, van Bokhoven H, 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(1):47–55PubMedCrossRefGoogle Scholar
  102. 102.
    Wysocka J, Swigut T, Milne TA, Dou Y, Zhang X, Burlingame AL, Roeder RG, Brivanlou AH, Allis CD (2005) WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121:859–872PubMedCrossRefGoogle Scholar
  103. 103.
    Kim SY, Levenson JM, Korsmeyer S, Sweatt JD, Schumacher A (2007) Developmental regulation of Eed complex composition governs a switch in global histone modification in brain. J Biol Chem 282:9962–9972PubMedCrossRefGoogle Scholar
  104. 104.
    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
  105. 105.
    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
  106. 106.
    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
  107. 107.
    Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ (2009) PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N{varepsilon}-dimethyl lysine demethylase. Hum Mol Genet 19(2):217–222Google Scholar
  108. 108.
    Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182–187PubMedCrossRefGoogle Scholar
  109. 109.
    Halpain S, Spencer K, Graber S (2005) Dynamics and pathology of dendritic spines. Prog Brain Res 147:29–37PubMedCrossRefGoogle Scholar
  110. 110.
    Jones FS, Meech R (1999) Knockout of REST/NRSF shows that the protein is a potent repressor of neuronally expressed genes in non-neural tissues. Bioessays 21:372–376PubMedCrossRefGoogle Scholar
  111. 111.
    Coulson JM (2005) Transcriptional regulation: cancer, neurons and the REST. Curr Biol 15:R665–R668PubMedCrossRefGoogle Scholar
  112. 112.
    Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994PubMedCrossRefGoogle Scholar
  113. 113.
    Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040PubMedCrossRefGoogle Scholar
  114. 114.
    Chan DW, Wang Y, Wu M, Wong J, Qin J, Zhao Y (2009) Unbiased proteomic screen for binding proteins to modified lysines on histone H3. Proteomics 9:2343–2354PubMedCrossRefGoogle Scholar
  115. 115.
    Nottke A, Colaiacovo MP, Shi Y (2009) Developmental roles of the histone lysine demethylases. Development 136:879–889PubMedCrossRefGoogle Scholar
  116. 116.
    Lan F, Nottke AC, Shi Y (2008) Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol 20:316–325PubMedCrossRefGoogle Scholar
  117. 117.
    Lu X, Meng X, Morris CA, Keating MT (1998) A novel human gene, WSTF, is deleted in Williams syndrome. Genomics 54:241–249PubMedCrossRefGoogle Scholar
  118. 118.
    Schubert C (2009) The genomic basis of the Williams-Beuren syndrome. Cell Mol Life Sci 66:1178–1197PubMedCrossRefGoogle Scholar
  119. 119.
    Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A et al (2003) The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113:905–917PubMedCrossRefGoogle Scholar
  120. 120.
    Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K et al (2009) WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457:57–62PubMedCrossRefGoogle Scholar
  121. 121.
    Poot RA, Bozhenok L, van den Berg DL, Steffensen S, Ferreira F, Grimaldi M, Gilbert N, Ferreira J, Varga-Weisz PD (2004) The Williams syndrome transcription factor interacts with PCNA to target chromatin remodelling by ISWI to replication foci. Nat Cell Biol 6:1236–1244PubMedCrossRefGoogle Scholar
  122. 122.
    Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM (1999) Structure and ligand of a histone acetyltransferase bromodomain. Nature 399:491–496PubMedCrossRefGoogle Scholar
  123. 123.
    Kato S, Fujiki R, Kim MS, Kitagawa H (2007) Ligand-induced transrepressive function of VDR requires a chromatin remodeling complex, WINAC. J Steroid Biochem Mol Biol 103:372–380PubMedCrossRefGoogle Scholar
  124. 124.
    Baker LA, Allis CD, Wang GG (2008) PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat Res 647:3–12PubMedCrossRefGoogle Scholar
  125. 125.
    Adams-Cioaba MA, Min J (2009) Structure and function of histone methylation binding proteins. Biochem Cell Biol 87:93–105PubMedCrossRefGoogle Scholar
  126. 126.
    Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD et al (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717PubMedCrossRefGoogle Scholar
  127. 127.
    Lan F, Collins RE, De Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y (2007) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448:718–722PubMedCrossRefGoogle Scholar
  128. 128.
    Field M, Tarpey PS, Smith R, Edkins S, O’Meara S, Stevens C, Tofts C, Teague J, Butler A, Dicks E et al (2007) Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am J Hum Genet 81:367–374PubMedCrossRefGoogle Scholar
  129. 129.
    Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB et al (2002) Mutations in PHF6 are associated with Borjeson-Forssman-Lehmann syndrome. Nat Genet 32:661–665PubMedCrossRefGoogle Scholar
  130. 130.
    Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AO et al (2004) Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 36:411–416PubMedCrossRefGoogle Scholar
  131. 131.
    Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM (1997) Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276:589–592PubMedCrossRefGoogle Scholar
  132. 132.
    Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ (2006) Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol Cell Biol 26:6880–6889PubMedCrossRefGoogle Scholar
  133. 133.
    Cao R, Tsukada Y, Zhang Y (2005) Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell 20:845–854PubMedCrossRefGoogle Scholar
  134. 134.
    Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y (2004) Role of histone H2A ubiquitination in Polycomb silencing. Nature 431:873–878PubMedCrossRefGoogle Scholar
  135. 135.
    de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M et al (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7:663–676PubMedCrossRefGoogle Scholar
  136. 136.
    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
  137. 137.
    Fan Z, Yamaza T, Lee JS, Yu J, Wang S, Fan G, Shi S, Wang CY (2009) BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol 11:1002–1009PubMedCrossRefGoogle Scholar
  138. 138.
    Brent MM, Marmorstein R (2008) Ankyrin for methylated lysines. Nat Struct Mol Biol 15:221–222PubMedCrossRefGoogle Scholar
  139. 139.
    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 15:245–250PubMedCrossRefGoogle Scholar
  140. 140.
    Winston F, Carlson M (1992) Yeast SNF/SWI transcriptional activators and the SPT/SIN chromatin connection. Trends Genet 8:387–391PubMedGoogle Scholar
  141. 141.
    Narlikar GJ, Fan HY, Kingston RE (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108:475–487PubMedCrossRefGoogle Scholar
  142. 142.
    Kingston RE, Narlikar GJ (1999) ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev 13:2339–2352PubMedCrossRefGoogle Scholar
  143. 143.
    Gibbons R (2006) Alpha thalassaemia-mental retardation, X linked. Orphanet J Rare Dis 1:15PubMedCrossRefGoogle Scholar
  144. 144.
    Gibbons RJ, Higgs DR (2000) Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet 97:204–212PubMedCrossRefGoogle Scholar
  145. 145.
    Gibbons RJ, Picketts DJ, Villard L, Higgs DR (1995) Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80:837–845PubMedCrossRefGoogle Scholar
  146. 146.
    McDowell TL, Gibbons RJ, Sutherland H, O’Rourke DM, Bickmore WA, Pombo A, Turley H, Gatter K, Picketts DJ, Buckle VJ et al (1999) Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes. Proc Natl Acad Sci USA 96:13983–13988PubMedCrossRefGoogle Scholar
  147. 147.
    Baumann C, De La Fuente R (2009) ATRX marks the inactive X chromosome (Xi) in somatic cells and during imprinted X chromosome inactivation in trophoblast stem cells. Chromosoma 118:209–222PubMedCrossRefGoogle Scholar
  148. 148.
    Ritchie K, Seah C, Moulin J, Isaac C, Dick F, Berube NG (2008) Loss of ATRX leads to chromosome cohesion and congression defects. J Cell Biol 180:315–324PubMedCrossRefGoogle Scholar
  149. 149.
    Pidoux AL, Allshire RC (2005) The role of heterochromatin in centromere function. Philos Trans R Soc Lond B Biol Sci 360:569–579PubMedCrossRefGoogle Scholar
  150. 150.
    Allshire RC, Nimmo ER, Ekwall K, Javerzat JP, Cranston G (1995) Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev 9:218–233PubMedCrossRefGoogle Scholar
  151. 151.
    Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis S, Bird A (2007) Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc Natl Acad Sci USA 104:2709–2714PubMedCrossRefGoogle Scholar
  152. 152.
    Gibbons RJ, McDowell TL, Raman S, O’Rourke DM, Garrick D, Ayyub H, Higgs DR (2000) Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24:368–371PubMedCrossRefGoogle Scholar
  153. 153.
    Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X et al (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691PubMedCrossRefGoogle Scholar
  154. 154.
    Pagon RA, Graham JM Jr, Zonana J, Yong SL (1981) Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99:223–227PubMedCrossRefGoogle Scholar
  155. 155.
    Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC et al (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36:955–957PubMedCrossRefGoogle Scholar
  156. 156.
    Sanlaville D, Verloes A (2007) CHARGE syndrome: an update. Eur J Hum Genet 15:389–399PubMedCrossRefGoogle Scholar
  157. 157.
    Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP (2005) Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum Mol Genet 14:3463–3476PubMedCrossRefGoogle Scholar
  158. 158.
    Schnetz MP, Bartels CF, Shastri K, Balasubramanian D, Zentner GE, Balaji R, Zhang X, Song L, Wang Z, Laframboise T et al (2009) Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res 19:590–601PubMedCrossRefGoogle Scholar
  159. 159.
    Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, Janecke AR, Tariverdian G, Chelly J, Fryns JP et al (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
  160. 160.
    Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C et al (2005) Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet 42:780–786PubMedCrossRefGoogle Scholar
  161. 161.
    Borjeson M, Forssman H, Lehmann O (1962) An X-linked, recessively inherited syndrome characterized by grave mental deficiency, epilepsy, and endocrine disorder. Acta Med Scand 171:13–21PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Department of PathologyHarvard Medical SchoolBostonUSA
  2. 2.Division of Newborn Medicine, Department of MedicineChildren’s Hospital BostonBostonUSA

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