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Understanding the epigenetics of neurodevelopmental disorders and DOHaD

  • T. Kubota (a1), K. Miyake (a1), N. Hariya (a1) and K. Mochizuki (a2)


The Developmental Origins of Health and Disease (DOHaD) hypothesis refers to the concept that ‘malnutrition during the fetal period induces a nature of thrift in fetuses, such that they have a higher change of developing non-communicable diseases, such as obesity and diabetes, if they grow up in the current well-fed society.’ Epigenetics is a chemical change in DNA and histones that affects how genes are expressed without alterations of DNA sequences. Several lines of evidence suggest that malnutrition during the fetal period alters the epigenetic expression status of metabolic genes in the fetus and that this altered expression can persist, and possibly lead to metabolic disorders. Similarly, mental stress during the neonatal period can alter the epigenetic expression status of neuronal genes in neonates. Moreover, such environmental, stress-induced, epigenetic changes are transmitted to the next generation via an acquired epigenetic status in sperm. The advantage of epigenetic modifications over changes in genetic sequences is their potential reversibility; thus, epigenetic alterations are potentially reversed with gene expression. Therefore, we potentially establish ‘preemptive medicine,’ that, in combination with early detection of abnormal epigenetic status and early administration of epigenetic-restoring drugs may prevent the development of disorders associated with the DOHaD.


Corresponding author

*Address for correspondence: T. Kubota, Department of Epigenetic Medicine, Fuculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. (Email:


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1. Inoue, K, Kanai, M, Tanabe, Y, et al. Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus–Merzbacher disease. Prenat Diagn. 2001; 21, 11331136.
2. Reiner, O, Carrozzo, R, Shen, Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing g protein beta-subunit-like repeats. Nature. 1993; 364, 717721.
3. Bi, W, Sapir, T, Shchelochkov, OA, et al. Increased LIS1 expression affects human and mouse brain development. Nat Genet. 2009; 41, 168177.
4. Online Mendelian Inheritance in Man (OMIM): #118220. Retrieved 31 January 2015 from http://www ncbi nlm nih gov/entrez/
5. Obi, T, Nishioka, K, Ross, OA, et al. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology. 2008; 70, 238241.
6. Waddington, CH. Epigenotype. Endeavour. 1942; 1, 1820.
7. Sharma, S, Kelly, TK, Jones, PA. Epigenetics in cancer. Carcinogenesis. 2010; 31, 2736.
8. Kubota, T, Das, S, Christian, SL, et al. Methylation-specific PCR simplifies imprinting analysis. Nat Genet. 1997; 16, 1617.
9. Nicholls, RD, Saitoh, S, Horsthemke, B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 1998; 14, 194200.
10. Duker, AL, Ballif, BC, Bawle, EV, et al. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome. Eur J Hum Genet. 2010; 18, 11961201.
11. Runte, M, Kroisel, PM, Gillessen-Kaesbach, G, et al. SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome. Hum Genet. 2004; 114, 553561.
12. Kubota, T, Saitoh, S, Matsumoto, T, et al. Excess functional copy of allele at chromosomal region 11p15 may cause Wiedemann-Beckwith (EMG) syndrome. Am J Med Genet. 1994; 49, 378383.
13. Gene Reviews (internet): Beckwith-Wiedemann syndrome. Retrieved 31 January 2015 from
14. Kubota, T, Wakui, K, Nakamura, T, et al. Proportion of the cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females. Cytogenet Genome Res. 2002; 99, 276284.
15. Kubota, T, Nonoyama, S, Tonoki, H, et al. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet. 1999; 104, 4955.
16. Sasaki, H, Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet. 2008; 9, 129140.
17. Sakashita, K, Koike, K, Kinoshita, T, et al. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001; 108, 11951204.
18. Lillycrop, KA, Phillips, ES, Jackson, AA, Hanson, MA, Burdge, GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005; 135, 13821386.
19. Lillycrop, KA, Phillips, ES, Torrens, C, et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr. 2008; 100, 278282.
20. Weaver, IC, Cervoni, N, Champagne, FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7, 847854.
21. Nolen, LD, Gao, S, Han, Z, et al. X chromosome reactivation and regulation in cloned embryos. Dev Biol. 2005; 279, 525540.
22. Okano, M, Bell, DW, Haber, DA, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99, 247257.
23. Shirohzu, H, Kubota, T, Kumazawa, A, et al. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am J Med Genet. 2002; 112, 3137.
24. Kubota, T, Furuumi, H, Kamoda, T, et al. ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation. Am J Med Genet. A. 2004; 129, 290293.
25. Tatton-Brown, K, Seal, S, Ruark, E, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014; 46, 385388.
26. Amir, RE, Van den Veyver, IB, Wan, M, et al. Rett syndrome is caused by mutations in X-linked MECP2 encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23, 185188.
27. Chunshu, Y, Endoh, K, Soutome, M, et al. A patient with classic Rett syndrome with a novel mutation in MECP2 exon 1. Clin Genet. 2006; 70, 530531.
28. Miyake, K, Hirasawa, T, Soutome, M, et al. The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome. BMC Neurosci. 2011; 12, 81.
29. Lumey, LH. Decreased birthweights in infants after maternal in utero exposure to the Dutch famine of 1944-1945. Paediatr Perinat Epidemiol. 1992; 6, 240253.
30. Painter, RC, de Rooij, SR, Bossuyt, PM, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2006; 84, 322327.
31. St Clair, D, Xu, M, Wang, P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA. 2005; 294, 557562.
32. Gluckman, PD, Seng, CY, Fukuoka, H, Beedle, AS, Hanson, MA. Low birthweight and subsequent obesity in Japan. Lancet. 2007; 369, 10811082.
33. Tobi, EW, Lumey, LH, Talens, RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009; 18, 40464053.
34. Lim, D, Bowdin, SC, Tee, L. Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. Hum Reprod. 2009; 24, 741747.
35. Tee, L, Lim, DH, Dias, RP, et al. Epimutation profiling in Beckwith-Wiedemann syndrome: relationship with assisted reproductive technology. Clin Epigenetics. 2013; 5, 23.
36. McGowan, PO, Sasaki, A, D’Alessio, AC, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009; 12, 342348.
37. Murgatroyd, C, Patchev, AV, Wu, Y, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009; 12, 15591566.
38. Kim, YS, Leventhal, BL, Koh, YJ, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011; 168, 904912.
39. Tsankova, NM, Berton, O, Renthal, W, et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006; 9, 519525.
40. Jessberger, S, Nakashima, K, Clemenson, GD Jr, et al. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci. 2007; 27, 59675975.
41. Dong, E, Nelson, M, Grayson, DR, Costa, E, Guidotti, A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci USA. 2008; 105, 1361413619.
42. Dong, E, Chen, Y, Gavin, DP, Grayson, DR, Guidotti, A. Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. Epigenetics. 2010; 5, 730735.
43. Wang, Q, Xu, X, Li, J, et al. Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. Cell Res. 2011; 21, 14241435.
44. Ma, DK, Jang, MH, Guo, JU, et al. Neuronal activity–induced gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009; 323, 10741077.
45. Breitling, LP, Yang, R, Korn, B, Burwinkel, B, Brenner, H. Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. Am J Hum Genet. 2011; 88, 450457.
46. Shenker, NS, Polidoro, S, van Veldhoven, K, et al. Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet. 2013; 22, 843851.
47. Waterland, RA, Jirtle, RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003; 23, 52935300.
48. Rimland, B. Controversies in the treatment of autistic children: vitamin and drug therapy. J Child Neurol. 1988; 3(Suppl.), S68S72.
49. James, SJ, Cutler, P, Melnyk, S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004; 80, 16111617.
50. Moretti, P, Sahoo, T, Hyland, K, et al. Cerebral folate deficiency with developmental delay; autism; and response to folinic acid. Neurology. 2005; 64, 10881090.
51. Kucharski, R, Maleszka, J, Foret, S, Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science. 2008; 319, 18271830.
52. Yaoi, T, Itoh, K, Nakamura, K, et al. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem Biophys Res Commun. 2008; 376, 563567.
53. Gore, AC, Walker, DM, Zama, AM, Armenti, AE, Uzumcu, M. Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol Endocrinol. 2011; 25, 21572168.
54. Ma, DK, Jang, MH, Guo, JU, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009; 323, 10741077.
55. Ling, C, Rönn, T. Epigenetic adaptation to regular exercise in humans. Drug Discov Today. 2014; 19, 10151018.
56. Kondo, M, Gray, LJ, Pelka, GJ, et al. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome-Mecp2 gene dosage effects and BDNF expression. Eur J Neurosci. 2008; 27, 33423350.
57. Lonetti, G, Angelucci, A, Morando, L, et al. Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol Psychiatry. 2010; 67, 657665.
58. Nag, N, Moriuchi, JM, Peitzman, CG, et al. Environmental enrichment alters locomotor behaviour and ventricular volume in MeCP2 1lox mice. Behav Brain Res. 2009; 196, 4448.
59. Kerr, B, Silva, PA, Walz, K, Young, JI. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome. PLoS One. 2010; 5, e11534.
60. Luikenhuis, S, Giacometti, E, Beard, CF, Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA. 2004; 101, 60336038.
61. Guy, J, Gan, J, Selfridge, J, Cobb, S, Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007; 315, 11431147.
62. Lioy, DT, Garg, SK, Monaghan, CE, et al. A role for glia in the progression of Rett’s syndrome. Nature. 2011; 475, 497500.
63. Vecsler, M, Simon, AJ, Amariglio, N, Rechavi, G, Gak, E. MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro. Epigenetics. 2010; 5, 6167.
64. Abel, T, Zukin, RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol. 2008; 8, 5764.
65. Cassel, S, Carouge, D, Gensburger, C, et al. Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. Mol Pharmacol. 2006; 70, 487492.
66. Popp, C, Dean, W, Feng, S, et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2011; 463, 11011105.
67. Daxinger, L, Whitelaw, E. Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 2010; 20, 16231628.
68. Horsthemke, B. Heritable germline epimutations in humans. Nat Genet. 2007; 39, 573574.
69. Rakyan, VK, Chong, S, Champ, ME, et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA. 2003; 100, 25382543.
70. Relton, CL, Davey Smith, G. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol. 2012; 41, 161176.
71. Kappeler, L, Meaney, MJ. Epigenetics and parental effects. Bioessays. 2010; 32, 818827.
72. Waterland, RA, Travisano, M, Tahiliani, KG. Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J. 2007; 21, 33803385.
73. Anway, MD, Cupp, AS, Uzumcu, M, Skinner, MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308, 14661469, Erratum in: Science. 2010; 328, 690.
74. Manikkam, M, Tracey, R, Guerrero-Bosagna, C, Skinner, MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One. 2013; 8, e55387.
75. Seong, KH, Li, D, Shimizu, H, Nakamura, R, Ishii, S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011; 145, 10491061.
76. Franklin, TB, Russig, H, Weiss, IC, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry. 2010; 68, 408415.
77. Champagne, FA, Weaver, IC, Diorio, J, et al. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006; 147, 29092915.
78. Martínez, D, Pentinat, T, Ribó, S, et al. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered lxra DNA methylation. Cell Metab. 2014; 19, 941951.
79. Jones, B. Epigenetics: transgenerational effects of in utero malnutrition. Nat Rev Genet. 2014; 15, 364.
80. Xu, C, Spragni, E, Jacques, V, Rsche, JR, Gottesfeld, JM. Improved histone deacetylase inhibitors as therapeutics for the neurodegenerative disease Friedreich’s ataxia: a new synthetic route. Pharmaceuticals. 2011; 4, 15781590.
81. leiman, SF, Berlin, J, Basso, M, et al. Histone deacetylase inhibitors and mitramycin a impact a similar neuroprotective pathway at a crossroad between cancer and neurodegeneration. Pharmaceuticals. 2011; 4, 11831185.
82. Wiers, CE. Methylation and the human brain: towards a new discipline of imaging epigenetics. Eur Arch Psychiatry Clin Neurosci. 2012; 262, 271273.
83. Lista, S, Garaci, FG, Toschi, N, Hampel, H. Imaging epigenetics in Alzheimer’s disease. Curr Pharm Des. 2013; 19, 63936415.
84. Wang, Y, Zhang, YL, Hennig, K, et al. Class I HDAC imaging using [(3)H]CI-994 autoradiography. Epigenetics. 2013; 8, 756764.
85. Wang, C, Schroeder, FA, Hooker, JM. Visualizing epigenetics: current advances and advantages in HDAC PET imaging techniques. Neuroscience. 2014; 264, 186197.



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