Abnormalities of the DNA Methylation Mark and Its Machinery: An Emerging Cause of Neurologic Dysfunction

 

 Buy Article Permissions and Reprints

Abstract

Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned “writers” and also the “readers” of the methyl mark, such as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency or overexpression of DNA methylation machinery leads to widespread gene expression changes in trans, disrupting expression of a subset of target genes that contribute to individual disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome have been thought generally to cause epigenetic dysregulation in cis. However, the recent description of multilocus methylation disorders challenges this generalization. Here, in addition to summarizing recent developments in identifying the pathogenesis of these diseases, we highlight clinical considerations and some unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical imprinting disorders.

• References

• 1 Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 2009; 8 (11) 1056-1072
  CrossrefPubMedGoogle Scholar
• 2 Bird A. Perceptions of epigenetics. Nature 2007; 447 (7143) 396-398
  CrossrefPubMedGoogle Scholar
• 3 Weichenhan D, Plass C. The evolving epigenome. Hum Mol Genet 2013; 22 (Suppl. 01) R1-R6
  CrossrefPubMedGoogle Scholar
• 4 Conerly M, Grady WM. Insights into the role of DNA methylation in disease through the use of mouse models. Dis Model Mech 2010; 3 (5-6) 290-297
  CrossrefPubMedGoogle Scholar
• 5 Eckhardt F, Lewin J, Cortese R , et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 2006; 38 (12) 1378-1385
  CrossrefPubMedGoogle Scholar
• 6 Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006; 31 (2) 89-97
  CrossrefPubMedGoogle Scholar
• 7 Chahrour M, Jung SY, Shaw C , et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 2008; 320 (5880) 1224-1229
  CrossrefPubMedGoogle Scholar
• 8 Guo JU, Su Y, Shin JH , et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 2014; 17 (2) 215-222
  PubMedGoogle Scholar
• 9 Mehler MF. Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 2008; 86 (4) 305-341
  CrossrefPubMedGoogle Scholar
• 10 Fahrner JA, Bjornsson HT. Mendelian disorders of the epigenetic machinery: Tipping the balance of chromatin states. Annu Rev Genomics Hum Genet 2014; 15 (September), in press
  PubMedGoogle Scholar
• 11 Maze I, Noh KM, Allis CD. Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 2013; 38 (1) 3-22
  CrossrefPubMedGoogle Scholar
• 12 Bjornsson HT, Brown LJ, Fallin MD , et al. Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors. J Natl Cancer Inst 2007; 99 (16) 1270-1273
  CrossrefPubMedGoogle Scholar
• 13 Ratnakumar K, Bernstein E. ATRX: the case of a peculiar chromatin remodeler. Epigenetics 2013; 8 (1) 3-9
  CrossrefPubMedGoogle Scholar
• 14 Walton EL, Francastel C, Velasco G. Maintenance of DNA methylation: Dnmt3b joins the dance. Epigenetics 2011; 6 (11) 1373-1377
  CrossrefPubMedGoogle Scholar
• 15 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005; 74: 481-514
  CrossrefPubMedGoogle Scholar
• 16 Klein CJ, Botuyan MV, Wu Y , et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 2011; 43 (6) 595-600
  CrossrefPubMedGoogle Scholar
• 17 Winkelmann J, Lin L, Schormair B , et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 2012; 21 (10) 2205-2210
  CrossrefPubMedGoogle Scholar
• 18 Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 2004; 20 (8) 350-358
  CrossrefPubMedGoogle Scholar
• 19 Berdasco M, Esteller M. Genetic syndromes caused by mutations in epigenetic genes. Hum Genet 2013; 132 (4) 359-383
  CrossrefPubMedGoogle Scholar
• 20 Tatton-Brown K, Seal S, Ruark E , et al; Childhood Overgrowth Consortium. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet 2014; 46 (4) 385-388
  CrossrefPubMedGoogle Scholar
• 21 Hagleitner MM, Lankester A, Maraschio P , et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 2008; 45 (2) 93-99
  PubMedGoogle Scholar
• 22 Matarazzo MR, De Bonis ML, Vacca M, Della Ragione F, D'Esposito M. Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome. Int J Biochem Cell Biol 2009; 41 (1) 117-126
  CrossrefPubMedGoogle Scholar
• 23 Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99 (3) 247-257
  CrossrefPubMedGoogle Scholar
• 24 Ueda Y, Okano M, Williams C, Chen T, Georgopoulos K, Li E. Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome. Development 2006; 133 (6) 1183-1192
  CrossrefPubMedGoogle Scholar
• 25 Heyn H, Vidal E, Sayols S , et al. Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient. Epigenetics 2012; 7 (6) 542-550
  CrossrefPubMedGoogle Scholar
• 26 Jin B, Tao Q, Peng J , et al. 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 2008; 17 (5) 690-709
  CrossrefPubMedGoogle Scholar
• 27 Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 2002; 3 (9) 662-673
  CrossrefPubMedGoogle Scholar
• 28 Fan G, Hutnick L. Methyl-CpG binding proteins in the nervous system. Cell Res 2005; 15 (4) 255-261
  CrossrefPubMedGoogle Scholar
• 29 Boyes J, Bird A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 1991; 64 (6) 1123-1134
  CrossrefPubMedGoogle Scholar
• 30 Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 1998; 18 (11) 6538-6547
  PubMedGoogle Scholar
• 31 Sasai N, Nakao M, Defossez PA. Sequence-specific recognition of methylated DNA by human zinc-finger proteins. Nucleic Acids Res 2010; 38 (15) 5015-5022
  CrossrefPubMedGoogle Scholar
• 32 Bogdanović O, Veenstra GJ. DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 2009; 118 (5) 549-565
  CrossrefPubMedGoogle Scholar
• 33 Mackay DJ, Callaway JL, Marks SM , et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 2008; 40 (8) 949-951
  CrossrefPubMedGoogle Scholar
• 34 de Greef JC, Wang J, Balog J , et al. Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am J Hum Genet 2011; 88 (6) 796-804
  CrossrefPubMedGoogle Scholar
• 35 Nitta H, Unoki M, Ichiyanagi K , et al. Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. J Hum Genet 2013; 58 (7) 455-460
  CrossrefPubMedGoogle Scholar
• 36 Weemaes CM, van Tol MJ, Wang J , et al. Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects. Eur J Hum Genet 2013; 21 (11) 1219-1225
  CrossrefPubMedGoogle Scholar
• 37 Laget S, Joulie M, Le Masson F , et al. The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA. PLoS ONE 2010; 5 (8) e11982
  CrossrefPubMedGoogle Scholar
• 38 Hodge JC, Mitchell E, Pillalamarri V , et al. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry 2014; 19 (3) 368-379
  CrossrefPubMedGoogle Scholar
• 39 Mullegama S, Rosenfeld J, Orellana C , et al. MBD5 dosage affects multiple neurodevelopmental pathways in common with other genetic syndromes. Presented at the American Society of Human Genetics Meeting; Nov 6-10, 2012; San Francisco, CA
  PubMed
• 40 Bonnet C, Ali Khan A, Bresso E , et al. Extended spectrum of MBD5 mutations in neurodevelopmental disorders. Eur J Hum Genet 2013; 21 (12) 1457-1461
  CrossrefPubMedGoogle Scholar
• 41 Mullegama SV, Rosenfeld JA, Orellana C , et al. Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Eur J Hum Genet 2014; 22 (1) 57-63
  CrossrefPubMedGoogle Scholar
• 42 Weng SM, Bailey ME, Cobb SR. Rett syndrome: from bed to bench. Pediatr Neonatol 2011; 52 (6) 309-316
  CrossrefPubMedGoogle Scholar
• 43 Nan X, Ng HH, Johnson CA , et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393 (6683) 386-389
  CrossrefPubMedGoogle Scholar
• 44 Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23 (2) 185-188
  CrossrefPubMedGoogle Scholar
• 45 Neul JL, Kaufmann WE, Glaze DG , et al; RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 2010; 68 (6) 944-950
  CrossrefPubMedGoogle Scholar
• 46 Liyanage VR, Rastegar M. Rett syndrome and MeCP2. Neuromolecular Med 2014; 16 (2) 231-264
  CrossrefPubMedGoogle Scholar
• 47 Naidu S, Bibat G, Kratz L , et al. Clinical variability in Rett syndrome. J Child Neurol 2003; 18 (10) 662-668
  CrossrefPubMedGoogle Scholar
• 48 Leuzzi V, Di Sabato ML, Zollino M, Montanaro ML, Seri S. Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation. Neurology 2004; 63 (10) 1968-1970
  CrossrefPubMedGoogle Scholar
• 49 Schüle B, Armstrong DD, Vogel H, Oviedo A, Francke U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet 2008; 74 (2) 116-126
  CrossrefPubMedGoogle Scholar
• 50 Moog U, Van Roozendaal K, Smeets E , et al. MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients. Brain Dev 2006; 28 (5) 305-310
  CrossrefPubMedGoogle Scholar
• 51 Van Esch H, Bauters M, Ignatius J , et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 2005; 77 (3) 442-453
  CrossrefPubMedGoogle Scholar
• 52 Cuddapah VA, Pillai RB, Shekar KV , et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet 2014; 51 (3) 152-158
  CrossrefPubMedGoogle Scholar
• 53 Cohen DR, Matarazzo V, Palmer AM , et al. Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol Cell Neurosci 2003; 22 (4) 417-429
  CrossrefPubMedGoogle Scholar
• 54 Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 2001; 27 (3) 327-331
  CrossrefPubMedGoogle Scholar
• 55 Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 2001; 27 (3) 322-326
  CrossrefPubMedGoogle Scholar
• 56 Chapleau CA, Calfa GD, Lane MC , et al. Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis 2009; 35 (2) 219-233
  CrossrefPubMedGoogle Scholar
• 57 Fukuda T, Itoh M, Ichikawa T, Washiyama K, Goto Y. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol 2005; 64 (6) 537-544
  PubMedGoogle Scholar
• 58 Li Y, Wang H, Muffat J , et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell 2013; 13 (4) 446-458
  CrossrefPubMedGoogle Scholar
• 59 Zhou Z, Hong EJ, Cohen S , et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006; 52 (2) 255-269
  CrossrefPubMedGoogle Scholar
• 60 Chen WG, Chang Q, Lin Y , et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003; 302 (5646) 885-889
  CrossrefPubMedGoogle Scholar
• 61 Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 2006; 21 (1) 217-227
  CrossrefPubMedGoogle Scholar
• 62 Chao HT, Zoghbi HY, Rosenmund C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 2007; 56 (1) 58-65
  CrossrefPubMedGoogle Scholar
• 63 Blue ME, Naidu S, Johnston MV. Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome. Exp Neurol 1999; 156 (2) 345-352
  CrossrefPubMedGoogle Scholar
• 64 Blue ME, Naidu S, Johnston MV. Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Ann Neurol 1999; 45 (4) 541-545
  CrossrefPubMedGoogle Scholar
• 65 Blue ME, Kaufmann WE, Bressler J , et al. Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice. Anat Rec (Hoboken) 2011; 294 (10) 1624-1634
  CrossrefPubMedGoogle Scholar
• 66 Lim DH, Maher ER. Human imprinting syndromes. Epigenomics 2009; 1 (2) 347-369
  CrossrefPubMedGoogle Scholar
• 67 Bartolomei MS. Genomic imprinting: employing and avoiding epigenetic processes. Genes Dev 2009; 23 (18) 2124-2133
  CrossrefPubMedGoogle Scholar
• 68 Chamberlain SJ. RNAs of the human chromosome 15q11-q13 imprinted region. Wiley Interdiscip Rev RNA 2013; 4 (2) 155-166
  CrossrefPubMedGoogle Scholar
• 69 Buiting K, Gross S, Lich C, Gillessen-Kaesbach G, el-Maarri O, Horsthemke B. Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 2003; 72 (3) 571-577
  CrossrefPubMedGoogle Scholar
• 70 Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genet Med 2010; 12 (7) 385-395
  CrossrefPubMedGoogle Scholar
• 71 Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of Angelman syndrome. Pediatr Neurol 2013; 48 (4) 271-279
  CrossrefPubMedGoogle Scholar
• 72 Leyser M, Penna PS, de Almeida AC, Vasconcelos MM, Nascimento OJ. Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome. Neurol Sci 2014; 35 (5) 701-705
  PubMedGoogle Scholar
• 73 Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997; 15 (1) 70-73
  CrossrefPubMedGoogle Scholar
• 74 Nawaz Z, Lonard DM, Smith CL , et al. The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol 1999; 19 (2) 1182-1189
  PubMedGoogle Scholar
• 75 Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet 2008; 17 (1) 111-118
  PubMedGoogle Scholar
• 76 Gustin RM, Bichell TJ, Bubser M , et al. Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome. Neurobiol Dis 2010; 39 (3) 283-291
  CrossrefPubMedGoogle Scholar
• 77 Jana NR. Understanding the pathogenesis of Angelman syndrome through animal models. Neural Plast 2012; 2012: 710943
  PubMedGoogle Scholar
• 78 Weeber EJ, Jiang YH, Elgersma Y , et al. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci 2003; 23 (7) 2634-2644
  PubMedGoogle Scholar
• 79 Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 2011; 34 (6) 293-303
  CrossrefPubMedGoogle Scholar
• 80 Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R. MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet 2005; 14 (8) 1049-1058
  CrossrefPubMedGoogle Scholar
• 81 Gentile JK, Tan WH, Horowitz LT , et al. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr 2010; 31 (7) 592-601
  PubMedGoogle Scholar
• 82 Lossie AC, Whitney MM, Amidon D , et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001; 38 (12) 834-845
  CrossrefPubMedGoogle Scholar
• 83 Varela MC, Kok F, Otto PA, Koiffmann CP. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet 2004; 12 (12) 987-992
  CrossrefPubMedGoogle Scholar
• 84 Eroglu A, Layman LC. Role of ART in imprinting disorders. Semin Reprod Med 2012; 30 (2) 92-104
  Article in Thieme ConnectPubMedGoogle Scholar
• 85 Eggermann T, Leisten I, Binder G, Begemann M, Spengler S. Disturbed methylation at multiple imprinted loci: an increasing observation in imprinting disorders. Epigenomics 2011; 3 (5) 625-637
  CrossrefPubMedGoogle Scholar
• 86 Azzi S, Rossignol S, Steunou V , et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet 2009; 18 (24) 4724-4733
  CrossrefPubMedGoogle Scholar
• 87 Turner CL, Mackay DM, Callaway JL , et al. Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci. Eur J Hum Genet 2010; 18 (6) 648-655
  CrossrefPubMedGoogle Scholar
• 88 Poole RL, Docherty LE, Al Sayegh A , et al; International Clinical Imprinting Consortium. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am J Med Genet A 2013; 161 (9) 2174-2182
  CrossrefPubMedGoogle Scholar
• 89 Garg SK, Lioy DT, Cheval H , et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J Neurosci 2013; 33 (34) 13612-13620
  CrossrefPubMedGoogle Scholar
• 90 Huang HS, Allen JA, Mabb AM , et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 2012; 481 (7380) 185-189
  PubMedGoogle Scholar