Epigenetic mechanisms and therapeutic perspectives for neurodevelopmental disorders

Pharmaceuticals

Volumn 5, Issue 4, 2012, Pages 369-383

  Kubota, Takeo ^a   Takae, Hirasawa ^a   Miyake, Kunio ^a  

^a UNIVERSITY OF YAMANASHI   (Japan)

Author keywords

DNA methylation; Drug; Environmental factor; Epigenetics; Histone modification; Neurodevelopmental disease; Reversible; Therapy

Indexed keywords

CRE RECOMBINASE; FOLIC ACID; IMIPRAMINE; TAMOXIFEN; VALPROIC ACID;

AGYRIA; ALPHA SYNUCLEIN GENE; CHILD ABUSE; CHILD NEGLECT; DEVELOPMENTAL DISORDER; DIET SUPPLEMENTATION; DNA METHYLATION; DNMT3 GENE; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG TARGETING; EARLY LIFE STRESS; EPIGENETICS; FOLIC ACID DEFICIENCY; GENE CONTROL; GENE DELETION; GENE DUPLICATION; GENE EXPRESSION; GENE IDENTIFICATION; GENE THERAPY; GENETIC CORRELATION; GENOME IMPRINTING; GR GENE; HAPPY PUPPET SYNDROME; HEREDITARY MOTOR SENSORY NEUROPATHY; HISTONE MODIFICATION; HUMAN; LIS1 GENE; MARKER GENE; MECP2 GENE; MENTAL STRESS; MUTATIONAL ANALYSIS; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; NR3C1 GENE; PARKINSON DISEASE; PELIZAEUS MERZBACHER DISEASE; PHARMACOGENOMICS; PLP1 GENE; PMP22 GENE; POINT MUTATION; RETT SYNDROME; REVIEW; UBE3A GENE; X CHROMOSOME INACTIVATION;

EID: 84860290513     PISSN: None     EISSN: 14248247     Source Type: Journal    
DOI: 10.3390/ph5040369     Document Type: Review

References (86)

1. McNairn, A.J.; Gilbert, D.M. Epigenomic replication: Linking epigenetics to DNA replication. Bioessays 2003, 25, 647-656.
2. Bestor, T.; Laudano, A.; Mattaliano, R.; Ingram, V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J. Mol. Biol. 1988, 203, 971-983.
3. Waddington, C.H. Epigenotype. Endeavour 1942, 1, 18-20.
4. Sharma, S.; Kelly, T.K.; Jones, P.A. Epigenetics in cancer. Carcinogenesis 2010, 31, 27-36.
5. Inoue, K.; Kanai, M.; Tanabe, Y.; Kubota, T.; Kashork, C.D.; Wakui, K.; Fukushima, Y.; Lupski, J.R.; Shaffer, L.G. Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease. Prenat. Diagn. 2001, 21, 1133-1136.
6. Reiner, O.; Carrozzo, R.; Shen, Y.; Wehnert, M.; Faustinella, F.; Dobyns, W.B.; Caskey, C.T.; Ledbetter, D.H. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 1993, 364, 717-721.
7. Bi, W.; Sapir, T.; Shchelochkov, O.A.; Zhang, F.; Withers, M.A.; Hunter, J.V.; Levy, T.; Shinder, V.; Peiffer, D.A.; Gunderson, K.L.; et al. Increased LIS1 expression affects human and mouse brain development. Nat. Genet. 2009, 41, 168-177.
8. Roa, B.B.; Lupski, J.R. Molecular basis of Charcot-Marie-Tooth disease type 1A: Gene dosage as a novel mechanism for a common autosomal dominant condition. Am. J. Med. Sci. 1993, 306, 177-184.
9. Obi, T.; Nishioka, K.; Ross, O.A.; Terada, T.; Yamazaki, K.; Sugiura, A.; Takanashi, M.; Mizoguchi, K.; Mori, H.; Mizuno, Y.; et al. Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology 2008, 70, 238-241.
10. Kubota, T.; Das, S.; Christian, S.L.; Baylin, S.B.; Herman, J.G.; Ledbetter, D.H. Methylation-specific PCR simplifies imprinting analysis. Nat. Genet. 1997, 16, 16-17.
11. Kubota, T.; Nonoyama, S.; Tonoki, H.; Masuno, M.; Imaizumi, K.; Kojima, M.; Wakui, K.; Shimadzu, M.; Fukushima, Y. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum. Genet. 1999, 104, 49-55.
12. Xue, F.; Tian, X.C.; Du, F.; Kubota, C.; Taneja, M.; Dinnyes, A.; Dai, Y. Levine, H.; Pereira, L.V.; Yang, X. Aberrant patterns of X chromosome inactivation in bovine clones. Nat. Genet. 2002, 31, 216-220.
13. Nolen, L.D.; Gao, S.; Han, Z.; Mann, M.R.; Gie, C.Y.; Otte, A.P.; Bartolomei, M.S.; Latham, K.E. X chromosome reactivation and regulation in cloned embryos. Dev. Biol. 2005, 279, 525-540.
14. Kubota, T.; Wakui, K.; Nakamura, T.; Ohashi, H.; Watanabe, Y. Yoshino, M.; Kida, T.; Okamoto, N.; Matsumura, M.; Muroya, K.; et al. The proportion of 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, 276-284.
15. Rodríguez, L.; Diego-Alvarez, D.; Lorda-Sanchez, I.; Gallardo, F.L.; Martínez-Fernández, M.L.; Arroyo-Muñoz, M.E.; Martínez-Frías, M.L. A small and active ring X chromosome in a female with features of Kabuki syndrome. Am. J. Med. Genet. A 2008, 146A, 2816-2821.
16. Okano, M.; Bell, D.W.; Haber, D.A.; Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99, 276-257.
17. Shirohzu, H.; Kubota, T.; Kumazawa, A.; Sado, T.; Chijiwa, T.; Inagaki, K.; Suetake, I.; Tajima, S.; Wakui, K.; Miki, Y.; et al. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am. J. Med. Genet. 2002, 112, 31-37.
18. Kubota, T.; Furuumi, H.; Kamoda, T.; Iwasaki, N.; Tobita, N.; Fujiwara, N.; Goto, Y. Matsui, A.; Sasaki, H.; Kajii, T. ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation. Am. J. Med. Genet. A 2004, 129A, 290-293.
19. Amir, R.E.; van den Veyver, I.B.; Wan, M.; Tran, C.Q.; Francke, U.; Zoghbi, H.Y. Rett syndrome is caused by mutations in X-linked MECP2; encoding methyl-CpG-binding protein 2. Nat. Genet. 1999, 23, 185-188.
20. Chunshu, Y.; Endoh, K.; Soutome, M.; Kawamura, R.; Kubota, T. A patient with classic Rett syndrome with a novel mutation in MECP2 exon 1. Clin. Genet. 2006, 70, 530-531.
21. Chen, W.G.; Chang, Q.; Lin, Y.; Meissner, A.; West, A.E.; Griffith, E.C.; Jaenisch, R.; Greenberg, M.E. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003, 302, 885-889.
22. Martinowich, K.; Hattori, D.; Wu, H.; Fouse, S.; He, F.; Hu, Y. Fan, G.; Sun, Y.E. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003, 302, 890-893.
23. Horike, S.; Cai, S.; Miyano, M.; Cheng, J.F.; Kohwi-Shigematsu, T. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat. Genet. 2005, 37, 31-40.
24. Itoh, M.; Ide, S.; Takashima, S.; Kudo, S.; Nomura, Y.; Segawa, M.; Kubota, T.; Mori, H.; Tanaka, S.; Horie, H.; et al. Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains. J. Neuropathol. Exp. Neurol. 2007, 66, 117-123.
25. Miyake, K.; Hirasawa, T.; Soutome, M.; Itoh, M.; Goto, Y. Endoh, K.; Takahashi, K.; Kudo, S.; Nakagawa, T.; Yokoi, S.; 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.
26. Basic investigation report for handicapped children 2005 (in Japanese). Available online: http://www.mhlw.go.jp/toukei/saikin/hw/titeki/index.html/ (accessed on 16 February 2012).
27. Yeargin-Allsopp, M.; Rice, C.; Karapurkar, T.; Doernberg, N.; Boyle, C.; Murphy, C. Prevalence of autism in a US metropolitan area. JAMA 2003, 289, 49-55.
28. Holoden, C. Autism now. Science 2009, 323, 565.
29. Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 2009, 65, 591-598.
30. Kim, Y.S.; Leventhal, B.L.; Koh, Y.J.; Fombonne, E.; Laska, E.; Lim, E.C.; Cheon, K.A.; Kim, S.J.; Kim, Y.K.; Lee, H.; et al. Prevalence of autism spectrum disorders in a total population sample. Am. J. Psychiatry 2011, 168, 904-912.
31. Lord, C. Epidemiology: How common is autism? Nature 2011, 474, 166-168.
32. Zoghbi, H.Y. Postnatal neurodevelopmental disorders: Meeting at the synapse? Science 2003, 302, 862-830.
33. Persico, A.M.; Bourgeron, T. Searching for ways out of the autism maze: Genetic, epigenetic and environmental clues. Trends Neurosci. 2006, 29, 349-358.
34. Arlt, M.F.; Mulle, J.G.; Schaibley, V.M.; Ragland, R.L.; Durkin, S.G.; Warren, S.T.; Glover, T.W. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am. J. Hum. Genet. 2009, 84, 339-350.
35. Qiu, J. Epigenetics: Unfinished symphony. Nature 2006, 441, 143-145.
36. Weaver, I.C.; Cervoni, N.; Champagne, F.A.; D'Alessio, A.C.; Sharma, S.; Seckl, J.R.; Dymov, S.; Szyf, M.; Meaney, M.J. Epigenetic programming by maternal behavior. Nat. Neurosci. 2004, 7, 847-854.
37. McGowan, P.O.; Sasaki, A.; D'Alessio, A.C.; Dymov, S.; Labonté, B.; Szyf, M.; Turecki, G.; Meaney, M.J. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 2009, 12, 342-348.
38. Murgatroyd, C.; Patchev, A.V.; Wu, Y.; Micale, V.; Bockmühl, Y.; Fischer, D.; Holsboer, F.; Wotjak, C.T.; Almeida, O.F.; Spengler, D. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurosci. 2009, 12, 1559-1566.
39. Claes, B.; Buysschaert, I.; Lambrechts, D. Pharmaco-epigenomics: Discovering therapeutic approaches and biomarkers for cancer therapy. Heredity (Edinb) 2010, 105, 152-160
40. Spannhoff, A.; Hauser, A.T.; Heinke, R.; Sippl, W.; Jung, M. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 2009, 4, 1568-1582.
41. Tsankova, N.M.; Berton, O.; Renthal, W.; Kumar, A.; Neve, R.L.; Nestler, E.J. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 2006, 9, 519-525.
42. Jessberger, S.; Nakashima, K.; Clemenson, G.D., Jr.; Mejia, E.; Mathews, E.; Ure, K.; Ogawa, S.; Sinton, C.M.; Gage, F.H.; Hsieh, J. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J. Neurosci. 2007, 27, 5967-5975.
43. Renthal, W.; Nestler, E.J. Epigenetic mechanisms in drug addiction. Trends Mol. Med. 2008, 14, 341-350.
44. Xu, C.; Spragni, E.; Jacques, V. Rsche, J.R.; Gottesfeld, J.M. Improved histone deacetylase inhibitors as therapeutics for the neurodegenerative disease Friedreich's ataxia: A new synthetic route. Pharmaceuticals 2011, 4, 1578-1590.
45. Sleiman, S.F.; Berlin, J.; Basso, M.; Karuppagounder, S.S.; Rohr, J.; Ratan, R.R. Histone deacetylase inhibitors and Mitramycin A impact a similar neuroprotective pathway at a crossroad between cancer and neurodegeneration. Pharmaceuticals 2011, 4, 1183-1185.
46. Csoka, A.B.; Szyf, M. Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology. Med. Hypotheses 2009, 73, 770-780.
47. Watanabe, H.; Fukuoka, H.; Sugiyama, T.; Nagai, Y.; Ogasawara, K.; Yoshiike, N. Dietary folate intake during pregnancy and birth weight in Japan. Eur. J. Nutr. 2008, 47, 341-347.
48. Hsieh, H.Y.; Chiu, P.H.; Wang, S.C. Epigenetics in traditional chinese pharmacy: A bioinformatic study at pharmacopoeia scale. Evid. Based Complement. Alternat. Med. 2011, 2011, 816714.
49. Dietrich, M.; Brown, C.J.; Block, G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J. Am. Coll. Nutr. 2005, 24, 266-274.
50. Ichi, S.; Costa, F.F.; Bischof, J.M.; Nakazaki, H.; Shen, Y.W.; Boshnjaku, V. Sharma, S.; Mania-Farnell, B.; McLone, D.G.; Tomita, T.; et al. Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development. J. Biol. Chem. 2010, 285, 36922-36932.
51. Park, J.H.; Stoffers, D.A.; Nicholls, R.D.; Simmons, R.A. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest. 2008, 118, 2316-2324.
52. Lillycrop, K.A.; Phillips, E.S.; Jackson, A.A.; Hanson, M.A.; Burdge, G.C. 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, 1382-1386.
53. Lillycrop, K.A.; Slater-Jefferies, J.L.; Hanson, M.A.; Godfrey, K.M.; Jackson, A.A.; Burdge, G.C. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modification. Br. J. Nutr. 2007, 97, 1064-1073.
54. Burdge, G.C.; Lillycrop, K.A.; Phillips, E.S.; Slater-Jefferies, J.L.; Jackson, A.A.; Hanson, M.A. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J. Nutr. 2009, 139, 1054-1060.
55. Rimland, B. Controversies in the treatment of autistic children: Vitamin and drug therapy. J. Child. Neurol. 1988, 3, S68-S72.
56. James, S.J.; Cutler, P.; Melnyk, S.; Jernigan, S.; Janak, L.; Gaylor, D.W.; Neubrander, J.A. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 2004, 20, 1611-1617.
57. Moretti, P.; Sahoo, T.; Hyland, K.; Bottiglieri, T.; Peters, S.; del Gaudio, D.; Roa, B.; Curry, S.; Zhu, H.; Finnell, R.H.; et al. Cerebral folate deficiency with developmental delay; autism; and response to folinic acid. Neurology 2005, 64, 1088-1090.
58. Kucharski, R.; Maleszka, J.; Foret, S.; Maleszka, R. Nutritional control of reproductive status in haneybees via DNA methylation. Science 2008, 319, 1827-1830.
59. Guy, J.; Hendrich, B.; Holmes, M.; Martin, J.E.; Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 2001, 27, 322-326.
60. Guy, J.; Gan, J.; Selfridge, J.; Cobb, S.; Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007, 315, 1143-1147.
61. Xin, Z.; Tachibana, M.; Guggiari, M.; Heard, E.; Shinkai, Y.; Wagstaff, J. Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center. J. Biol. Chem. 2003, 278, 14996-15000.
62. Iwase, S.; Lan, F.; Bayliss, P.; de la Torre-Ubieta, L.; Huarte, M.; Qi, H.H.; Whetstine, J.R.; Bonni, A.; Roberts, T.M.; Shi, Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 2007, 128, 1077-1088.
63. Qi, H.H.; Sarkissian, M.; Hu, G.Q.; Wang, Z.; Bhattacharjee, A.; Gordon, D.B.; Gonzales, M.; Lan, F.; Ongusaha, P.P.; Huarte, M.; et al. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 2010, 466, 503-507.
64. Huang, H.S.; Allen, J.A.; Mabb, A.M.; King, I.F.; Miriyala, J.; Taylor-Blake, B.; Sciaky, N.; Dutton, J.W., Jr.; Lee, H.M.; Chen, X.; et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 2011, 481, 185-189.
65. Matsuda, H.; Fukuda, N.; Ueno, T.; Katakawa, M.; Wang, X.; Watanabe, T.; Matsui, S.; Aoyama, T.; Saito, K.; Bando, T.; et al. Transcriptional inhibition of progressive renal disease by gene silencing pyrrole-imidazole polyamide targeting of the transforming growth factor-β1 promoter. Kidney Int. 2011, 79, 46-56.
66. Ohtsuki, A.; Kimura, M.T.; Minoshima, M.; Suzuki, T.; Ikeda, M.; Bando, T.; Nagase, H.; Shinohara, K.; Sugiyama, H. Synthesis and properties of PI polyamide-SAHA conjugate. Tetrahedron Lett. 2009, 50, 7288-7292.
67. Kondo, M.; Gray, L.J.; Pelka, G.J.; Christodoulou, J.; Tam, P.P.; Hannan, A.J. 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, 3342-3350.
68. Nag, N.; Moriuchi, J.M.; Peitzman, C.G.; Ward, B.C.; Kolodny, N.H.; Berger-Sweeney, J.E. Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp2 1lox mice. Behav. Brain Res. 2009, 196, 44-48.
69. Kerr, B.; Silva, P.A.; Walz, K.; Young, J.I. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome. PLoS One 2010, 5, e11534.
70. Lonetti, G.; Angelucci, A.; Morando, L.; Boggio, E.M.; Giustetto, M.; Pizzorusso, T. Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol. Psychiatry 2010, 67, 657-665.
71. Woods, R.; Vallero, R.O.; Golub, M.S.; Suarez, J.K.; Ta, T.A.; Yasui, D.H.; Chi, L.H.; Kostyniak, P.J.; Pessah, I.N.; Berman, R.F.; et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2 308 mutation. Hum. Mol. Genet. 2012, doi:10.1093/hmg/dds046.
72. Horsthemke, B. Heritable germline epimutations in humans. Nat. Genet. 2007, 39, 573-574.
73. Daxinger, L.; Whitelaw, E. Transgenerational epigenetic inheritance: More questions than answers. Genome. Res. 2010, 20, 1623-1628.
74. Seong, K.H.; Li, D.; Shimizu, H.; Nakamura, R.; Ishii, S. Inheritance of stress-induced; ATF-2-dependent epigenetic change. Cell 2011. 145, 1049-1061.
75. Anway, M.D.; Cupp, A.S.; Uzumcu, M.; Skinner, M.K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005, 308, 1466-1469.
76. Yaoi, T.; Itoh, K.; Nakamura, K.; Ogi, H.; Fujiwara, Y. Fushiki, S. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem. Biophys. Res. Commun. 2008, 376, 563-567.
77. Gore, A.C.; Walker, D.M.; Zama, A.M.; Armenti, A.E.; Uzumcu, M. Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol. Endocrinol. 2011, 25, 2157-2168.
78. Kumar, A.; Choi, K.H.; Renthal, W.; Tsankova, N.M.; Theobald, D.E.; Truong, H.T.; Russo, S.J.; Laplant, Q.; Sasaki, T.S.; Whistler, K.N.; et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005, 48, 303-314.
79. Pascual, M.; Boix, J.; Felipo, V.; Guerri, C. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J. Neurochem. 2009, 108, 920-931.
80. Franklin, T.B.; Russig, H.; Weiss, I.C.; Gräff, J.; Linder, N.; Michalon, A.; Vizi, S.; Mansuy, I.M. Epigenetic transmission of the impact of early stress across generations. Biol. Psychiatry 2010, 68, 408-415.
81. Thayer, Z.M.; Kuzawa, C.W. Biological memories of past environments: Epigenetic pathways to health disparities. Epigenetics 2011, 6, 798-803.
82. Arai, J.A.; Feig, L.A. Long-lasting and transgenerational effects of an environmental enrichment on memory formation. Brain Res. Bull. 2011, 85, 30-35.
83. Sakazume, S.; Ohashi, H.; Sasaki, Y.; Harada, N.; Nakanishi, K.; Sato, H.; Emi, M.; Endoh, K.; Sohma, R.; Kido, Y.; et al. Spread of X-chromosome inactivation into chromosome 15 is associated with Prader-Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation. Hum. Genet. 2012, 131, 121-130.
84. Breitling, L.P.; Yang, R.; Korn, B.; Burwinkel, B.; Brenner, H. Tobacco-smoking-related differential DNA methylation: 27K Discovery and replication. Am. J. Hum. Genet. 2011, 88, 450-457.
85. Poon, L.L.; Leung, T.N.; Lau, T.K.; Chow, K.C.; Lo, Y.M. Differential DNA methylation between fetus and mother as a strategy for detecting fetal DNA in maternal plasma. Clin. Chem. 2002, 48, 35-41.
86. Papageorgiou, E.A.; Karagrigoriou, A.; Tsaliki, E.; Velissariou, V.; Carter, N.P.; Patsalis, P.C. Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. Nat. Med. 2011, 17, 510-513.