Mendelian disorders of the epigenetic machinery are a newly delineated group of multiple congenital anomaly and intellectual disability syndromes resulting from mutations in genes encoding components of the epigenetic machinery. The gene products affected in these inherited conditions act in and are expected to have widespread epigenetic consequences. Many of these syndromes demonstrate phenotypic overlap with classical imprinting disorders and with one another. The various writer and eraser systems involve opposing players, which we propose must maintain a balance between open and closed chromatin states in any given cell. An imbalance might lead to disrupted expression of disease-relevant target genes. We suggest that classifying disorders based on predicted effects on this balance would be informative regarding pathogenesis. Furthermore, strategies targeted at restoring this balance might offer novel therapeutic avenues, taking advantage of available agents such as histone deacetylase inhibitors and histone acetylation antagonists.


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Literature Cited

  1. Alarcón JM, Malleret G, Touzani K, Vronskaya S, Ishii S. 1.  et al. 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 42:947–59 [Google Scholar]
  2. Altarejos JY, Montminy M. 2.  2011. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12:141–51 [Google Scholar]
  3. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U. 3.  et al. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:185–88 [Google Scholar]
  4. Arnaud P, Feil R. 4.  2005. Epigenetic deregulation of genomic imprinting in human disorders and following assisted reproduction. Birth Defects Res. C 75:81–97 [Google Scholar]
  5. Azad N, Zahnow CA, Rudin CM, Baylin SB. 5.  2013. The future of epigenetic therapy in solid tumours—lessons from the past. Nat. Rev. Clin. Oncol. 10:256–66 [Google Scholar]
  6. Bannister AJ, Kouzarides T. 6.  1996. The CBP co-activator is a histone acetyltransferase. Nature 384:641–43 [Google Scholar]
  7. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO. 7.  et al. 2001. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410:120–24 [Google Scholar]
  8. Barlow DP. 8.  2011. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45:379–403 [Google Scholar]
  9. Bartolomei MS, Ferguson-Smith AC. 9.  2011. Mammalian genomic imprinting. Cold Spring Harb. Perspect. Biol. 3:a002592 [Google Scholar]
  10. Baylin SB, Jones PA. 10.  2011. A decade of exploring the cancer epigenome—biological and translational implications. Nat. Rev. Cancer 11:726–34 [Google Scholar]
  11. Berdasco M, Esteller M. 11.  2013. Genetic syndromes caused by mutations in epigenetic genes. Hum. Genet. 132:359–83 [Google Scholar]
  12. Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P. 12.  et al. 2009. Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc. Natl. Acad. Sci. USA 106:21830–35 [Google Scholar]
  13. Berger SL. 13.  2007. The complex language of chromatin regulation during transcription. Nature 447:407–12 [Google Scholar]
  14. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ. 14.  et al. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–26 [Google Scholar]
  15. Beutler AS, Li S, Nicol R, Walsh MJ. 15.  2005. Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 76:3107–15 [Google Scholar]
  16. Bird AP. 16.  1986. CpG-rich islands and the function of DNA methylation. Nature 321:209–13 [Google Scholar]
  17. Bjornsson HT, Fallin MD, Feinberg AP. 17.  2004. An integrated epigenetic and genetic approach to common human disease. Trends Genet. 20:350–58 [Google Scholar]
  18. Black JC, Van Rechem C, Whetstine JR. 18.  2012. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48:491–507 [Google Scholar]
  19. Breuning MH, Dauwerse HG, Fugazza G, Saris JJ, Spruit L. 19.  et al. 1993. Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. Am. J. Hum. Genet. 52:249–54 [Google Scholar]
  20. Buck-Koehntop BA, Defossez PA. 20.  2013. On how mammalian transcription factors recognize methylated DNA. Epigenetics 8:131–37 [Google Scholar]
  21. Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman OA. 21.  et al. 2012. Mutations in KAT6B, encoding a histone acetyltransferase, cause genitopatellar syndrome. Am. J. Hum. Genet. 90:282–89 [Google Scholar]
  22. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. 22.  2012. Prader-Willi syndrome. Genet. Med. 14:10–26 [Google Scholar]
  23. Cea M, Cagnetta A, Gobbi M, Patrone F, Richardson PG. 23.  et al. 2013. New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr. Pharm. Des. 19:734–44 [Google Scholar]
  24. Choufani S, Shuman C, Weksberg R. 24.  2013. Molecular findings in Beckwith-Wiedemann syndrome. Am. J. Med. Genet. C 163C:131–40 [Google Scholar]
  25. Clayton-Smith J, O'Sullivan J, Daly S, Bhaskar S, Day R. 25.  et al. 2011. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am. J. Hum. Genet. 89:675–81 [Google Scholar]
  26. Clynes D, Higgs DR, Gibbons RJ. 26.  2013. The chromatin remodeller ATRX: a repeat offender in human disease. Trends Biochem. Sci. 38:461–66 [Google Scholar]
  27. Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T. 27.  et al. 2012. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesion acetylation cycle. Nature 489:313–17 [Google Scholar]
  28. Denslow SA, Wade PA. 28.  2007. The human Mi-2/NuRD complex and gene regulation. Oncogene 26:5433–38 [Google Scholar]
  29. Eggermann T, Begemann M, Spengler S, Schröder C, Kordass U. 29.  et al. 2010. Genetic and epigenetic findings in Silver-Russell syndrome. Pediatr. Endocrinol. Rev. 8:86–93 [Google Scholar]
  30. Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC. 30.  et al. 1982. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 10:2709–21 [Google Scholar]
  31. Eissenberg JC, Shilatifard A. 31.  2010. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev. Biol. 339:240–49 [Google Scholar]
  32. 32. ENCODE Proj. Consort 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816 [Google Scholar]
  33. Eustermann S, Yang JC, Law MJ, Amos R, Chapman LM. 33.  et al. 2011. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. Nat. Struct. Mol. Biol. 18:777–82 [Google Scholar]
  34. Feinberg AP. 34.  2007. Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–40 [Google Scholar]
  35. Ficz G, Heintzmann R, Arndt-Jovin DJ. 35.  2005. Polycomb group protein complexes exchange rapidly in living Drosophila. Development 132:3963–76 [Google Scholar]
  36. Field M, Tarpey PS, Smith R, Edkins S, O'Meara S. 36.  et al. 2007. Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am. J. Hum. Genet. 81:367–74 [Google Scholar]
  37. Gardner KE, Allis CD, Strahl BD. 37.  2011. Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409:36–46 [Google Scholar]
  38. Gibbons RJ. 38.  2006. Alpha thalassaemia-mental retardation, X linked. Orphanet J. Rare Dis. 1:15 [Google Scholar]
  39. Gibbons RJ, Picketts DJ, Villard L, Higgs DR. 39.  1995. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome). Cell 80:837–45 [Google Scholar]
  40. Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ. 40.  et al. 2008. Mutations in the chromatin-associated protein ATRX. Hum. Mutat. 29:796–802 [Google Scholar]
  41. Gibson WT, Hood RL, Zhan SH, Bulman DE, Fejes AP. 41.  et al. 2012. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90:110–18 [Google Scholar]
  42. Greer EL, Shi Y. 42.  2012. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13:343–57 [Google Scholar]
  43. Gregor A, Oti M, Kouwenhoven EN, Hoyer J, Sticht H. 43.  et al. 2013. De novo mutations in the genome organizer CTCF cause intellectual disability. Am. J. Hum. Genet. 93:124–31 [Google Scholar]
  44. Guo C, Chang CC, Wortham M, Chen LH, Kernagis DN. 44.  et al. 2012. Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways. Proc. Natl. Acad. Sci. USA 109:17603–8 [Google Scholar]
  45. Guy J, Cheval H, Selfridge J, Bird A. 45.  2011. The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27:631–52 [Google Scholar]
  46. Hackett JA, Surani MA. 46.  2013. DNA methylation dynamics during the mammalian life cycle. Philos. Trans. R. Soc. Lond. B 368:20110328 [Google Scholar]
  47. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK. 47.  et al. 1999. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. USA 96:14412–17 [Google Scholar]
  48. Harakalova M, van den Boogaard MJ, Sinke R, van Lieshout S, van Tuil MC. 48.  et al. 2012. X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. J. Med. Genet. 49:539–43 [Google Scholar]
  49. Hargreaves DC, Crabtree GR. 49.  2011. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21:396–420 [Google Scholar]
  50. Hellman A, Chess A. 50.  2007. Gene body-specific methylation on the active X chromosome. Science 315:1141–43 [Google Scholar]
  51. Hock H. 51.  2012. A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev. 26:751–55 [Google Scholar]
  52. Hodge JC, Mitchell E, Pillalamarri V, Toler TL, Bartel F. 52.  et al. 2014. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol. Psychiatry 19:368–79 [Google Scholar]
  53. Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C. 53.  et al. 2012. Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. Am. J. Hum. Genet. 90:308–13 [Google Scholar]
  54. Hoyer J, Ekici AB, Endele S, Popp B, Zweier C. 54.  et al. 2012. Haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a frequent cause of intellectual disability. Am. J. Hum. Genet. 90:565–72 [Google Scholar]
  55. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C. 55.  et al. 2009. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 41:178–86 [Google Scholar]
  56. Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM. 56.  et al. 2006. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol. Cell. Biol. 27:1889–903 [Google Scholar]
  57. Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW. 57.  et al. 2011. ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. Nat. Struct. Mol. Biol. 18:769–76 [Google Scholar]
  58. Iyer LM, Tahiliani M, Rao A, Aravind L. 58.  2009. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8:1698–710 [Google Scholar]
  59. Jaenisch R, Bird A. 59.  2003. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33:Suppl.245–54 [Google Scholar]
  60. Jensen LR, Amende M, Gurok U, Moser B, Gimmel V. 60.  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. 76:227–36 [Google Scholar]
  61. Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV. 61.  et al. 2012. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am. J. Hum. Genet. 91:358–64 [Google Scholar]
  62. Jørgensen HF, Bird A. 62.  2002. MeCP2 and other methyl-CpG binding proteins. Ment. Retard. Dev. Disabil. Res. Rev. 8:87–93 [Google Scholar]
  63. Kamimura J, Endo Y, Kurotaki N, Kinoshita A, Miyake N. 63.  et al. 2003. Identification of eight novel NSD1 mutations in Sotos syndrome. J. Med. Genet. 40:e126 [Google Scholar]
  64. Kantor B, Makedonski K, Shemer R, Razin A. 64.  2003. Expression and localization of components of the histone deacetylases multiprotein repressory complexes in the mouse preimplantation embryo. Gene Expr. Patterns 3:697–702 [Google Scholar]
  65. Kasper LH, Lerach S, Wang J, Wu S, Jeevan T. 65.  et al. 2010. CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation. EMBO J. 29:3660–72 [Google Scholar]
  66. Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM. 66.  et al. 2006. Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am. J. Hum. Genet. 79:370–77 [Google Scholar]
  67. Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA. 67.  et al. 2011. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat. Genet. 43:595–600 [Google Scholar]
  68. Korzus E, Rosenfeld MG, Mayford M. 68.  2004. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–72 [Google Scholar]
  69. Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T. 69.  et al. 2002. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30:365–66 [Google Scholar]
  70. Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S. 70.  et al. 2005. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J. Med. Genet. 42:780–86 [Google Scholar]
  71. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M. 71.  et al. 2012. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Hum. Genet. 90:119–24 [Google Scholar]
  72. Lee JT, Bartolomei MS. 72.  2013. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152:1308–23 [Google Scholar]
  73. Liu J, Kim J, Oberdoerffer P. 73.  2013. Metabolic modulation of chromatin: implications for DNA repair and genomic integrity. Front. Genet. 4:182 [Google Scholar]
  74. Lopez-Atalaya JP, Gervasini C, Mottadelli F, Spena S, Piccione M. 74.  et al. 2012. Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome. J. Med. Genet. 49:66–74 [Google Scholar]
  75. Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA. 75.  et al. 2002. Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome. Nat. Genet. 32:661–65 [Google Scholar]
  76. Lu C, Thompson CB. 76.  2012. Metabolic regulation of epigenetics. Cell Metab. 16:9–17 [Google Scholar]
  77. Mabb AM, Judson MC, Zylka MJ, Philpot BD. 77.  2011. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci. 34:293–303 [Google Scholar]
  78. Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL. 78.  et al. 2008. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat. Genet. 40:949–51 [Google Scholar]
  79. Manzo F, Tambaro FP, Mai A, Altucci L. 79.  2009. Histone acetyltransferase inhibitors and preclinical studies. Expert Opin. Ther. Pat. 19:761–74 [Google Scholar]
  80. Matarazzo MR, De Bonis ML, Vacca M, Della Ragione F, D'Esposito M. 80.  2009. Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome. Int. J. Biochem. Cell Biol. 41:117–26 [Google Scholar]
  81. Maze I, Noh KM, Allis CD. 81.  2013. Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 38:3–22 [Google Scholar]
  82. Mito Y, Henikoff JG, Henikoff S. 82.  2007. Histone replacement marks the boundaries of cis-regulatory domains. Science 315:1408–11 [Google Scholar]
  83. Moretti P, Zoghbi HY. 83.  2006. MeCP2 dysfunction in Rett syndrome and related disorders. Curr. Opin. Genet. Dev. 16:276–81 [Google Scholar]
  84. Morris B, Etoubleau C, Bourthoumieu S, Reynaud-Perrine S, Laroche C. 84.  et al. 2012. Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome. Am. J. Med. Genet. A 158A:2015–20 [Google Scholar]
  85. Mullegama SV, Rosenfeld JA, Orellana C, van Bon BW, Halbach S. 85.  et al. 2014. Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Eur. J. Hum. Genet. 22:57–63 [Google Scholar]
  86. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ. 86.  et al. 2010. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42:790–93 [Google Scholar]
  87. O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA. 87.  et al. 2001. The Polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol 21:4330–36 [Google Scholar]
  88. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. 88.  1996. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–59 [Google Scholar]
  89. Okitsu CY, Hsieh CL. 89.  2007. DNA methylation dictates histone H3K4 methylation. Mol. Cell. Biol. 27:2746–57 [Google Scholar]
  90. Ollikainen M, Craig JM. 90.  2011. Epigenetic discordance at imprinting control regions in twins. Epigenomics 3:295–306 [Google Scholar]
  91. Opitz JM, Weaver DW, Reynolds JF Jr. 91.  1998. The syndromes of Sotos and Weaver: reports and review. Am. J. Med. Genet. 79:294–304 [Google Scholar]
  92. Pastor WA, Aravind L, Rao A. 92.  2013. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 14:341–56 [Google Scholar]
  93. Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC. 93.  et al. 1995. Rubinstein-Taybi syndrome caused by mutations in the transcriptional coactivator CBP. Nature 376:348–51 [Google Scholar]
  94. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA. 94.  et al. 2001. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276:36734–41 [Google Scholar]
  95. Piccolo FM, Fisher AG. 95.  2014. Getting rid of DNA methylation. Trends Cell Biol. 24:136–43 [Google Scholar]
  96. Poole RL, Docherty LE, Al Sayegh A, Caliebe A, Turner C. 96.  et al. 2013. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am. J. Med. Genet. A 161:2174–82 [Google Scholar]
  97. Portela A, Esteller M. 97.  2010. Epigenetic modifications and human disease. Nat. Biotechnol. 28:1057–68 [Google Scholar]
  98. Qiu J, Shi G, Jia Y, Li J, Wu M. 98.  et al. 2010. The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell Res. 20:908–18 [Google Scholar]
  99. Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K. 99.  et al. 2003. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 22:3153–63 [Google Scholar]
  100. Razin A, Riggs AD. 100.  1980. DNA methylation and gene function. Science 210:604–10 [Google Scholar]
  101. Roelfsema JH, White SJ, Ariyürek Y, Bartholdi D, Niedrist D. 101.  et al. 2005. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am. J. Hum. Genet. 76:572–80 [Google Scholar]
  102. Ronan JL, Wu W, Crabtree GR. 102.  2013. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14:347–59 [Google Scholar]
  103. Rosenfeld MG, Lunyak VV, Glass CK. 103.  2006. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20:1405–28 [Google Scholar]
  104. Russo VEA, Martienssen RA, Riggs AD. 104.  1996. Epigenetic Mechanisms of Gene Regulation Woodbury, NY: Cold Spring Harb. Lab. Press [Google Scholar]
  105. Santen GW, Aten E, Sun Y, Almomani R, Gilissen C. 105.  et al. 2012. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat. Genet. 44:379–80 [Google Scholar]
  106. Santen GW, Aten E, Vulto-van Silfhout AT, Pottinger C, van Bon BW. 106.  et al. 2013. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum. Mutat. 34:1519–28 [Google Scholar]
  107. Schneppenheim R, Fruhwald MC, Gesk S, Hasselblatt M, Jeibmann A. 107.  et al. 2010. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am. J. Hum. Genet. 86:279–84 [Google Scholar]
  108. Schwartz YB, Pirrotta V. 108.  2008. Polycomb complexes and epigenetic states. Curr. Opin. Cell Biol. 20:266–73 [Google Scholar]
  109. Sengoku T, Yokoyama S. 109.  2011. Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A. Genes Dev. 25:2266–77 [Google Scholar]
  110. Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R. 110.  et al. 1999. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65:1342–48 [Google Scholar]
  111. Smith ZD, Meissner A. 111.  2013. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14:204–20 [Google Scholar]
  112. Strahl BD, Allis CD. 112.  2000. The language of covalent histone modifications. Nature 403:41–45 [Google Scholar]
  113. Swensen JJ, Keyser J, Coffin CM, Biegel JA, Viskochil DH. 113.  et al. 2009. Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J. Med. Genet. 46:68–72 [Google Scholar]
  114. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H. 114.  et al. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–35 [Google Scholar]
  115. Talkowski ME, Mullegama SV, Rosenfeld JA, van Bon BW, Shen Y. 115.  et al. 2011. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89:551–63 [Google Scholar]
  116. Tatton-Brown K, Hanks S, Ruark E, Zachariou A, Duarte Sdel V. 116.  et al. 2011. Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height. Oncotarget 2:1127–33 [Google Scholar]
  117. Tatton-Brown K, Rahman N. 117.  2013. The NSD1 and EZH2 overgrowth genes, similarities and differences. Am. J. Med. Genet. C 163C:86–91 [Google Scholar]
  118. Todd MA, Picketts DJ. 118.  2012. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex. J. Proteome Res. 11:4326–37 [Google Scholar]
  119. Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y. 119.  et al. 2012. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat. Genet. 44:376–78 [Google Scholar]
  120. Turner G, Gedeon A, Mulley J, Sutherland G, Rae J. 120.  et al. 1989. Börjeson-Forssman-Lehmann syndrome: clinical manifestations and gene localization to Xq26-27. Am. J. Med. Genet. 34:463–69 [Google Scholar]
  121. Urdinguio RG, Sanchez-Mut JV, Esteller M. 121.  2009. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8:1056–72 [Google Scholar]
  122. Valor LM, Pulopulos MM, Jimenez-Minchan M, Olivares R, Lutz B. 122.  et al. 2011. Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability. J. Neurosci. 31:1652–63 [Google Scholar]
  123. Van Houdt JKJ, Nowakowska BA, Sousa SB, van Schaik BDC, Seuntjens E. 123.  et al. 2012. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat. Genet. 44:445–49 [Google Scholar]
  124. Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X. 124.  et al. 2004. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119:555–66 [Google Scholar]
  125. Vissers LELM, van Ravenswaaij CMA, Admiraal R, Hurst JA, de Vries BBA. 125.  et al. 2004. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet. 36:955–57 [Google Scholar]
  126. Wagner EJ, Carpenter PB. 126.  2012. Understanding the language of Lys36 methylation at histone H3. Nat. Rev. Mol. Cell Biol. 13:115–26 [Google Scholar]
  127. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M. 127.  et al. 1999. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol. Cell. Biol. 19:7816–27 [Google Scholar]
  128. Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G. 128.  et al. 2010. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87:219–28 [Google Scholar]
  129. Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J. 129.  et al. 2012. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum. Mol. Genet. 21:2205–10 [Google Scholar]
  130. Wolffe AP. 130.  1994. Nucleosome positioning and modification: chromatin structures that potentiate transcription. Trends Biochem. Sci. 19:240–44 [Google Scholar]
  131. Wolffe AP, Matzke MA. 131.  1999. Epigenetics: regulation through repression. Science 286:481–86 [Google Scholar]
  132. Wood MA, Attner MA, Oliveira AM, Brindle PK, Abel T. 132.  2006. A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn. Mem. 13:609–17 [Google Scholar]
  133. Yang H, Pesavento JJ, Starnes TW, Cryderman DE, Wallrath LL. 133.  et al. 2008. Preferential dimethylation of histone H4 lysine 20 by Suv4-20. J. Biol. Chem. 283:12085–92 [Google Scholar]
  134. Yang X, Lay F, Han H, Jones PA. 134.  2010. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol. Sci. 31:536–46 [Google Scholar]
  135. Yuan W, Xu M, Huang C, Liu N, Chen S. 135.  et al. 2011. H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J. Biol. Chem. 286:7983–89 [Google Scholar]
  136. Yun M, Wu J, Workman JL, Li B. 136.  2011. Readers of histone modifications. Cell Res. 21:564–78 [Google Scholar]
  137. Zentner GE, Henikoff S. 137.  2013. Regulation of nucleosome dynamics by histone modifications. Nat. Struct. Mol. Biol. 20:259–66 [Google Scholar]
  138. Zuckerkandl E. 138.  1974. A possible role of “inert” heterochromatin in cell differentiation. Action of and competition for “locking” molecules. Biochimie 56:937–54 [Google Scholar]

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