Table of Contents Author Guidelines Submit a Manuscript
Stem Cells International
Volume 2016, Article ID 9464591, 16 pages
http://dx.doi.org/10.1155/2016/9464591
Review Article

Epigenetic Research of Neurodegenerative Disorders Using Patient iPSC-Based Models

1Laboratory of Neurodegenerative Disorders, Department of Clinical and Experimental Neurology, Hospital Clinic of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), 08036 Barcelona, Spain
2Centre for Networked Biomedical Research in Neurodegenerative Disorders (CIBERNED), 28031 Madrid, Spain
3Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), 08036 Barcelona, Spain

Received 17 April 2015; Accepted 18 June 2015

Academic Editor: Giuseppina Caretti

Copyright © 2016 Rubén Fernández-Santiago and Mario Ezquerra. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Stadtfeld and K. Hochedlinger, “Induced pluripotency: history, mechanisms, and applications,” Genes and Development, vol. 24, no. 20, pp. 2239–2263, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Takahashi, K. Tanabe, M. Ohnuki et al., “Induction of pluripotent stem cells from adult human fibroblasts by defined factors,” Cell, vol. 131, no. 5, pp. 861–872, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Vierbuchen, A. Ostermeier, Z. P. Pang, Y. Kokubu, T. C. Südhof, and M. Wernig, “Direct conversion of fibroblasts to functional neurons by defined factors,” Nature, vol. 463, no. 7284, pp. 1035–1041, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. S. Yamanaka and H. M. Blau, “Nuclear reprogramming to a pluripotent state by three approaches,” Nature, vol. 465, no. 7299, pp. 704–712, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. D. W. Han, N. Tapia, A. Hermann et al., “Direct reprogramming of fibroblasts into neural stem cells by defined factors,” Cell Stem Cell, vol. 10, no. 4, pp. 465–472, 2012. View at Publisher · View at Google Scholar · View at Scopus
  6. T. M. Dawson, H. S. Ko, and V. L. Dawson, “Genetic animal models of Parkinson's disease,” Neuron, vol. 66, no. 5, pp. 646–661, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. L. Qiang, R. Fujita, and A. Abeliovich, “Remodeling neurodegeneration: somatic cell reprogramming-based models of adult neurological disorders,” Neuron, vol. 78, no. 6, pp. 957–969, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. A. E. Lang and A. M. Lozano, “Parkinson's disease. Second of two parts,” The New England Journal of Medicine, vol. 339, no. 16, pp. 1130–1143, 1998. View at Publisher · View at Google Scholar · View at Scopus
  9. A. E. Lang and A. M. Lozano, “Parkinson's disease. First of two parts,” The New England Journal of Medicine, vol. 339, no. 15, pp. 1044–1053, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. I.-H. Park, N. Arora, H. Huo et al., “Disease-specific induced pluripotent stem cells,” Cell, vol. 134, no. 5, pp. 877–886, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. E. Hedlund, J. Pruszak, T. Lardaro et al., “Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease,” Stem Cells, vol. 26, no. 6, pp. 1526–1536, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Kriks, J.-W. Shim, J. Piao et al., “Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease,” Nature, vol. 480, no. 7378, pp. 547–551, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Wernig, J.-P. Zhao, J. Pruszak et al., “Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 15, pp. 5856–5861, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. R. Tandan and W. G. Bradley, “Amyotrophic lateral sclerosis: part 2. Etiopathogenesis,” Annals of Neurology, vol. 18, no. 4, pp. 419–431, 1985. View at Publisher · View at Google Scholar · View at Scopus
  15. R. Tandan and W. G. Bradley, “Amyotrophic lateral sclerosis: part I. Clinical features, pathology, and ethical issues in management,” Annals of Neurology, vol. 18, no. 3, pp. 271–280, 1985. View at Publisher · View at Google Scholar · View at Scopus
  16. L. Bäckman, T.-B. Robins-Wahlin, A. Lundin, N. Ginovart, and L. Farde, “Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes,” Brain, vol. 120, part 12, pp. 2207–2217, 1997. View at Publisher · View at Google Scholar · View at Scopus
  17. L. H. A. Watkins, R. D. Rogers, A. D. Lawrence, B. J. Sahakian, A. E. Rosser, and T. W. Robbins, “Impaired planning but intact decision making in early Huntington's disease: implications for specific fronto-striatal pathology,” Neuropsychologia, vol. 38, no. 8, pp. 1112–1125, 2000. View at Publisher · View at Google Scholar · View at Scopus
  18. C. Ballard, S. Gauthier, A. Corbett, C. Brayne, D. Aarsland, and E. Jones, “Alzheimer's disease,” The Lancet, vol. 377, no. 9770, pp. 1019–1031, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. M. J. Farrer, “Genetics of Parkinson disease: paradigm shifts and future prospects,” Nature Reviews Genetics, vol. 7, no. 4, pp. 306–318, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. R. L. Nussbaum and C. E. Ellis, “Alzheimer's disease and Parkinson's disease,” The New England Journal of Medicine, vol. 348, no. 14, pp. 1356–1364, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. B. Byers, B. Cord, H. N. Nguyen et al., “SNCA triplication parkinson's patient's iPSC-Derived DA neurons accumulate α-Synuclein and are susceptible to oxidative stress,” PLoS ONE, vol. 6, no. 11, Article ID e26159, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. O. Cooper, H. Seo, S. Andrabi et al., “Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease,” Science Translational Medicine, vol. 4, no. 141, Article ID 141ra90, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. H. Jiang, Y. Ren, E. Y. Yuen et al., “Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells,” Nature Communications, vol. 3, article 668, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. H. N. Nguyen, B. Byers, B. Cord et al., “LRRK2 mutant iPSC-derived da neurons demonstrate increased susceptibility to oxidative stress,” Cell Stem Cell, vol. 8, no. 3, pp. 267–280, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. A. Rakovic, K. Shurkewitsch, P. Seibler et al., “Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons,” Journal of Biological Chemistry, vol. 288, no. 4, pp. 2223–2237, 2013. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Reinhardt, B. Schmid, L. F. Burbulla et al., “Genetic correction of a lrrk2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression,” Cell Stem Cell, vol. 12, no. 3, pp. 354–367, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. S. D. Ryan, N. Dolatabadi, S. F. Chan et al., “Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1alpha transcription,” Cell, vol. 155, pp. 1351–1364, 2013. View at Google Scholar
  28. A. Sánchez-Danés, Y. Richaud-Patin, I. Carballo-Carbajal et al., “Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease,” EMBO Molecular Medicine, vol. 4, no. 5, pp. 380–395, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. D. C. Schöndorf, M. Aureli, F. E. McAllister et al., “iPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis,” Nature Communications, vol. 5, article 4028, 2014. View at Publisher · View at Google Scholar · View at Scopus
  30. P. Seibler, J. Graziotto, H. Jeong, F. Simunovic, C. Klein, and D. Krainc, “Mitochondrial parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells,” Journal of Neuroscience, vol. 31, no. 16, pp. 5970–5976, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Almeida, E. Gascon, H. Tran et al., “Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons,” Acta Neuropathologica, vol. 126, no. 3, pp. 385–399, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Chen, K. Qian, Z. Du et al., “Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons,” Cell Stem Cell, vol. 14, no. 6, pp. 796–809, 2014. View at Publisher · View at Google Scholar · View at Scopus
  33. A.-C. Devlin, K. Burr, S. Borooah et al., “Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability,” Nature Communications, vol. 6, article 5999, 2015. View at Publisher · View at Google Scholar · View at Scopus
  34. J. T. Dimos, K. T. Rodolfa, K. K. Niakan et al., “Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons,” Science, vol. 321, no. 5893, pp. 1218–1221, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. N. Egawa, S. Kitaoka, K. Tsukita et al., “Drug screening for ALS using patient-specific induced pluripotent stem cells,” Science Translational Medicine, vol. 4, no. 145, Article ID 145ra104, 2012. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Mitne-Neto, M. Machado-Costa, M. C. N. Marchetto et al., “Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients,” Human Molecular Genetics, vol. 20, no. 18, pp. 3642–3652, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. D. Sareen, J. G. O'Rourke, P. Meera et al., “Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion,” Science Translational Medicine, vol. 5, no. 208, Article ID 208ra149, 2013. View at Publisher · View at Google Scholar · View at Scopus
  38. M. C. An, N. Zhang, G. Scott et al., “Genetic correction of Huntington's disease phenotypes in induced pluripotent stem cells,” Cell Stem Cell, vol. 11, no. 2, pp. 253–263, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. The HD iPSC Consortium, “Induced pluripotent stem cells from patients with Huntington's disease show cag-repeat-expansion-associated phenotypes,” Cell Stem Cell, vol. 11, no. 2, pp. 264–278, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. I. Jeon, N. Lee, J.-Y. Li et al., “Neuronal properties, in vivo effects, and pathology of a Huntington's disease patient-derived induced pluripotent stem cells,” Stem Cells, vol. 30, no. 9, pp. 2054–2062, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Zhang, M. C. An, D. Montoro, and L. M. Ellerby, “Characterization of human Huntington's disease cell model from induced pluripotent stem cells,” PLoS Currents, vol. 2, Article ID RRN1193, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. M. A. Israel, S. H. Yuan, C. Bardy et al., “Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells,” Nature, vol. 482, no. 7384, pp. 216–220, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Kondo, M. Asai, K. Tsukita et al., “Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness,” Cell Stem Cell, vol. 12, no. 4, pp. 487–496, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. C. R. Muratore, H. C. Rice, P. Srikanth et al., “The familial alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons,” Human Molecular Genetics, vol. 23, no. 13, Article ID ddu064, pp. 3523–3536, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. T. Yagi, D. Ito, Y. Okada et al., “Modeling familial Alzheimer's disease with induced pluripotent stem cells,” Human Molecular Genetics, vol. 20, no. 23, pp. 4530–4539, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. Y. Bergman and H. Cedar, “DNA methylation dynamics in health and disease,” Nature Structural and Molecular Biology, vol. 20, no. 3, pp. 274–281, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. R. G. Urdinguio, J. V. Sanchez-Mut, and M. Esteller, “Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies,” The Lancet Neurology, vol. 8, no. 11, pp. 1056–1072, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. M. F. Mehler, “Epigenetics and the nervous system,” Annals of Neurology, vol. 64, no. 6, pp. 602–617, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. I. A. Qureshi and M. F. Mehler, “Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases,” Neurotherapeutics, vol. 11, no. 4, pp. 708–720, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. C. M. Rivera and B. Ren, “Mapping human epigenomes,” Cell, vol. 155, no. 1, pp. 39–55, 2013. View at Publisher · View at Google Scholar · View at Scopus
  51. S. L. Berger, T. Kouzarides, R. Shiekhattar, and A. Shilatifard, “An operational definition of epigenetics,” Genes and Development, vol. 23, no. 7, pp. 781–783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. R. R. Kanherkar, N. Bhatia-Dey, E. Makarev, and A. B. Csoka, “Cellular reprogramming for understanding and treating human disease,” Frontiers in Cell and Developmental Biology, vol. 2, article 67, 2014. View at Publisher · View at Google Scholar
  53. M. J. Ziller, H. Gu, F. Müller et al., “Charting a dynamic DNA methylation landscape of the human genome,” Nature, vol. 500, no. 7463, pp. 477–481, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. B. Weinhold, “Epigenetics: the science of change,” Environmental Health Perspectives, vol. 114, no. 3, pp. A160–A167, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. R. R. Kanherkar, N. Bhatia-Dey, and A. B. Csoka, “Epigenetics across the human lifespan,” Frontiers in Cell and Developmental Biology, vol. 2, article 49, 2014. View at Publisher · View at Google Scholar
  56. M. F. Fraga, E. Ballestar, M. F. Paz et al., “Epigenetic differences arise during the lifetime of monozygotic twins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10604–10609, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. C. Huidobro, A. F. Fernandez, and M. F. Fraga, “Aging epigenetics: causes and consequences,” Molecular Aspects of Medicine, vol. 34, no. 4, pp. 765–781, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. S.-C. Wang, B. Oeize, and A. Schumacher, “Age-specific epigenetic drift in late-onset Alzheimer's disease,” PLoS ONE, vol. 3, no. 7, Article ID e2698, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. K. E. Varley, J. Gertz, K. M. Bowling et al., “Dynamic DNA methylation across diverse human cell lines and tissues,” Genome Research, vol. 23, no. 3, pp. 555–567, 2013. View at Publisher · View at Google Scholar · View at Scopus
  60. W. Xie, C. L. Barr, A. Kim et al., “Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome,” Cell, vol. 148, no. 4, pp. 816–831, 2012. View at Publisher · View at Google Scholar · View at Scopus
  61. R. Lister, E. A. Mukamel, J. R. Nery et al., “Global epigenomic reconfiguration during mammalian brain development,” Science, vol. 341, no. 6146, Article ID 1237905, 2013. View at Publisher · View at Google Scholar · View at Scopus
  62. M. J. Ziller, F. Müller, J. Liao et al., “Genomic distribution and inter-sample variation of non-CpG methylation across human cell types,” PLoS Genetics, vol. 7, no. 12, Article ID e1002389, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. A. P. Feinberg, R. A. Irizarry, D. Fradin et al., “Personalized epigenomic signatures that are stable over time and covary with body mass index,” Science Translational Medicine, vol. 2, no. 49, Article ID 49ra67, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Feng, S. Fouse, and G. Fan, “Epigenetic regulation of neural gene expression and neuronal function,” Pediatric Research, vol. 61, no. 5, pp. 58R–63R, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. K.-S. Kang, “Epigenetic regulations in adult stem cells: the role of DNA methyltransferase in stem cell aging,” Epigenomics, vol. 3, no. 6, pp. 671–673, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. S. K. T. Ooi, C. Qiu, E. Bernstein et al., “DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA,” Nature, vol. 448, no. 7154, pp. 714–717, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. X.-R. Long, Y. He, C. Huang, and J. Li, “MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in hepatocellular carcinogenesis,” International Journal of Oncology, vol. 45, no. 6, pp. 1915–1922, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. B. L. Wienholz, M. S. Kareta, A. H. Moarefi, C. A. Gordon, P. A. Ginno, and F. Chédin, “DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo,” PLoS Genetics, vol. 6, no. 9, Article ID e1001106, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. K. Martins-Taylor, D. I. Schroeder, J. M. Lasalle, M. Lalande, and R.-H. Xu, “Role of DNMT3B in the regulation of early neural and neural crest specifiers,” Epigenetics, vol. 7, no. 1, pp. 71–82, 2012. View at Google Scholar · View at Scopus
  70. P. A. Jones and D. Takai, “The role of DNA methylation in mammalian epigenetics,” Science, vol. 293, no. 5532, pp. 1068–1070, 2001. View at Publisher · View at Google Scholar · View at Scopus
  71. R. J. Klose and A. P. Bird, “MeCP2 behaves as an elongated monomer that does not stably associate with the Sin3a chromatin remodeling complex,” The Journal of Biological Chemistry, vol. 279, no. 45, pp. 46490–46496, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Chahrour, Y. J. Sung, C. Shaw et al., “MeCP2, a key contributor to neurological disease, activates and represses transcription,” Science, vol. 320, no. 5880, pp. 1224–1229, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. D. H. Yasui, S. Peddada, M. C. Bieda et al., “Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 49, pp. 19416–19421, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Kulis, S. Heath, M. Bibikova et al., “Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia,” Nature Genetics, vol. 44, no. 11, pp. 1236–1242, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Tahiliani, K. P. Koh, Y. Shen et al., “Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1,” Science, vol. 324, no. 5929, pp. 930–935, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. D. G. Hernandez, M. A. Nalls, J. R. Gibbs et al., “Distinct DNA methylation changes highly correlated with chronological age in the human brain,” Human Molecular Genetics, vol. 20, no. 6, Article ID ddq561, pp. 1164–1172, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. R. E. Irwin, A. Thakur, K. M. O' Neill, and C. P. Walsh, “5-Hydroxymethylation marks a class of neuronal gene regulated by intragenic methylcytosine levels,” Genomics, vol. 104, no. 5, pp. 383–392, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. M. A. Hahn, R. Qiu, X. Wu et al., “Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis,” Cell Reports, vol. 3, no. 2, pp. 291–300, 2013. View at Publisher · View at Google Scholar · View at Scopus
  79. M. Münzel, D. Globisch, and T. Carell, “5-hydroxymethylcytosine, the sixth base of the genome,” Angewandte Chemie, vol. 50, no. 29, pp. 6460–6468, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. C. X. Song, K. E. Szulwach, Y. Fu et al., “Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine,” Nature Biotechnology, vol. 29, no. 1, pp. 68–75, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. K. E. Szulwach, X. Li, Y. Li et al., “5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging,” Nature Neuroscience, vol. 14, no. 12, pp. 1607–1616, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. N. Bhutani, J. J. Brady, M. Damian, A. Sacco, S. Y. Corbel, and H. M. Blau, “Reprogramming towards pluripotency requires AID-dependent DNA demethylation,” Nature, vol. 463, no. 7284, pp. 1042–1047, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Luger, A. W. Mäder, R. K. Richmond, D. F. Sargent, and T. J. Richmond, “Crystal structure of the nucleosome core particle at 2.8 A resolution,” Nature, vol. 389, no. 6648, pp. 251–260, 1997. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Kouzarides, “Chromatin modifications and their function,” Cell, vol. 128, no. 4, pp. 693–705, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. S. L. Berger, “The complex language of chromatin regulation during transcription,” Nature, vol. 447, no. 7143, pp. 407–412, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. M. P. Creyghton, A. W. Cheng, G. G. Welstead et al., “Histone H3K27ac separates active from poised enhancers and predicts developmental state,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21931–21936, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. N. D. Heintzman, G. C. Hon, R. D. Hawkins et al., “Histone modifications at human enhancers reflect global cell-type-specific gene expression,” Nature, vol. 459, no. 7243, pp. 108–112, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Visel, M. J. Blow, Z. Li et al., “ChIP-seq accurately predicts tissue-specific activity of enhancers,” Nature, vol. 457, no. 7231, pp. 854–858, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. C. Martin and Y. Zhang, “Mechanisms of epigenetic inheritance,” Current Opinion in Cell Biology, vol. 19, no. 3, pp. 266–272, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. B. E. Bernstein, A. Meissner, and E. S. Lander, “The mammalian epigenome,” Cell, vol. 128, no. 4, pp. 669–681, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Haberland, R. L. Montgomery, and E. N. Olson, “The many roles of histone deacetylases in development and physiology: implications for disease and therapy,” Nature Reviews Genetics, vol. 10, no. 1, pp. 32–42, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. V. W. Zhou, A. Goren, and B. E. Bernstein, “Charting histone modifications and the functional organization of mammalian genomes,” Nature Reviews Genetics, vol. 12, no. 1, pp. 7–18, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. B. Guillemette, P. Drogaris, H.-H. S. Lin et al., “H3 lysine 4 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation,” PLoS Genetics, vol. 7, no. 3, Article ID e1001354, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Verdone, E. Agricola, M. Caserta, and E. Di Mauro, “Histone acetylation in gene regulation,” Briefings in Functional Genomics and Proteomics, vol. 5, no. 3, pp. 209–221, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. Z. Wang, C. Zang, J. A. Rosenfeld et al., “Combinatorial patterns of histone acetylations and methylations in the human genome,” Nature Genetics, vol. 40, no. 7, pp. 897–903, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. M. D. Shahbazian and M. Grunstein, “Functions of site-specific histone acetylation and deacetylation,” Annual Review of Biochemistry, vol. 76, pp. 75–100, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. A. J. Ruthenburg, H. Li, D. J. Patel, and C. D. Allis, “Multivalent engagement of chromatin modifications by linked binding modules,” Nature Reviews Molecular Cell Biology, vol. 8, no. 12, pp. 983–994, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Ernst, P. Kheradpour, T. S. Mikkelsen et al., “Mapping and analysis of chromatin state dynamics in nine human cell types,” Nature, vol. 473, no. 7345, pp. 43–49, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. A. Kundaje, W. Meuleman, J. Ernst et al., “Integrative analysis of 111 reference human epigenomes,” Nature, vol. 518, pp. 317–330, 2015. View at Publisher · View at Google Scholar
  100. W. Xie, M. D. Schultz, R. Lister et al., “Epigenomic analysis of multilineage differentiation of human embryonic stem cells,” Cell, vol. 153, no. 5, pp. 1134–1148, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. R. D. Hawkins, G. C. Hon, L. K. Lee et al., “Distinct epigenomic landscapes of pluripotent and lineage-committed human cells,” Cell Stem Cell, vol. 6, no. 5, pp. 479–491, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. M. E. Hamby, V. Coskun, and Y. E. Sun, “Transcriptional regulation of neuronal differentiation: the epigenetic layer of complexity,” Biochimica et Biophysica Acta, vol. 1779, no. 8, pp. 432–437, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. M. F. Mehler, “Epigenetic principles and mechanisms underlying nervous system functions in health and disease,” Progress in Neurobiology, vol. 86, no. 4, pp. 305–341, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. K. B. Massirer, C. Carromeu, K. Griesi-Oliveira, and A. R. Muotri, “Maintenance and differentiation of neural stem cells,” Wiley Interdisciplinary Reviews: Systems Biology and Medicine, vol. 3, no. 1, pp. 107–114, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. T. Takizawa and E. Meshorer, “Chromatin and nuclear architecture in the nervous system,” Trends in Neurosciences, vol. 31, no. 7, pp. 343–352, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. J. Lessard, J. I. Wu, J. A. Ranish et al., “An essential switch in subunit composition of a chromatin remodeling complex during neural development,” Neuron, vol. 55, no. 2, pp. 201–215, 2007. View at Publisher · View at Google Scholar · View at Scopus
  107. M. B. Stadler, R. Murr, L. Burger et al., “DNA-binding factors shape the mouse methylome at distal regulatory regions,” Nature, vol. 480, no. 7378, pp. 490–495, 2011. View at Publisher · View at Google Scholar
  108. I. Cantone and A. G. Fisher, “Epigenetic programming and reprogramming during development,” Nature Structural and Molecular Biology, vol. 20, no. 3, pp. 282–289, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. C. A. Gifford, M. J. Ziller, H. Gu et al., “Transcriptional and epigenetic dynamics during specification of human embryonic stem cells,” Cell, vol. 153, no. 5, pp. 1149–1163, 2013. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Drouin, “Minireview: pioneer transcription factors in cell fate specification,” Molecular Endocrinology, vol. 28, no. 7, pp. 989–998, 2014. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Thomson, S. J. Liu, L.-N. Zou, Z. Smith, A. Meissner, and S. Ramanathan, “Pluripotency factors in embryonic stem cells regulate differentiation into germ layers,” Cell, vol. 145, no. 6, pp. 875–889, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. L. A. Boyer, I. L. Tong, M. F. Cole et al., “Core transcriptional regulatory circuitry in human embryonic stem cells,” Cell, vol. 122, no. 6, pp. 947–956, 2005. View at Publisher · View at Google Scholar · View at Scopus
  113. R. A. Young, “Control of the embryonic stem cell state,” Cell, vol. 144, no. 6, pp. 940–954, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. Y.-H. Loh, W. Zhang, X. Chen, J. George, and H.-H. Ng, “Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells,” Genes and Development, vol. 21, no. 20, pp. 2545–2557, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. B. M. Olynik and M. Rastegar, “The genetic and epigenetic journey of embryonic stem cells into mature neural cells,” Frontiers in Genetics, vol. 3, article 81, 2012. View at Publisher · View at Google Scholar · View at Scopus
  116. B. A. Barber and M. Rastegar, “Epigenetic control of Hox genes during neurogenesis, development, and disease,” Annals of Anatomy, vol. 192, no. 5, pp. 261–274, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. R. Margueron and D. Reinberg, “The Polycomb complex PRC2 and its mark in life,” Nature, vol. 469, no. 7330, pp. 343–349, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. G. P. Delcuve, M. Rastegar, and J. R. Davie, “Epigenetic control,” Journal of Cellular Physiology, vol. 219, no. 2, pp. 243–250, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. T. Burgold, F. Spreafico, F. De Santa et al., “The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment,” PLoS ONE, vol. 3, no. 8, Article ID e3034, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. S. U. Schmitz, M. Albert, M. Malatesta et al., “Jarid1b targets genes regulating development and is involved in neural differentiation,” The EMBO Journal, vol. 30, no. 22, pp. 4586–4600, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. M. J. Burney, C. Johnston, K.-Y. Wong et al., “An epigenetic signature of developmental potential in neural stem cells and early neurons,” Stem Cells, vol. 31, no. 9, pp. 1868–1880, 2013. View at Publisher · View at Google Scholar · View at Scopus
  122. J.-H. Lee, S. R. L. Hart, and D. G. Skalnik, “Histone deacetylase activity is required for embryonic stem cell differentiation,” Genesis, vol. 38, no. 1, pp. 32–38, 2004. View at Publisher · View at Google Scholar · View at Scopus
  123. E. Meshorer, D. Yellajoshula, E. George, P. J. Scambler, D. T. Brown, and T. Misteli, “Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells,” Developmental Cell, vol. 10, no. 1, pp. 105–116, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. A. M. Tsankov, H. Gu, V. Akopian et al., “Transcription factor binding dynamics during human ES cell differentiation,” Nature, vol. 518, no. 7539, pp. 344–349, 2015. View at Publisher · View at Google Scholar
  125. M. J. Ziller, R. Edri, Y. Yaffe et al., “Dissecting neural differentiation regulatory networks through epigenetic footprinting,” Nature, 2014. View at Publisher · View at Google Scholar · View at Scopus
  126. E. Apostolou and K. Hochedlinger, “Chromatin dynamics during cellular reprogramming,” Nature, vol. 502, no. 7472, pp. 462–471, 2013. View at Publisher · View at Google Scholar · View at Scopus
  127. T. Brambrink, R. Foreman, G. G. Welstead et al., “Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells,” Cell Stem Cell, vol. 2, no. 2, pp. 151–159, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. M. Stadtfeld, N. Maherali, D. T. Breault, and K. Hochedlinger, “Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse,” Cell Stem Cell, vol. 2, no. 3, pp. 230–240, 2008. View at Publisher · View at Google Scholar · View at Scopus
  129. Y. Buganim, D. A. Faddah, and R. Jaenisch, “Mechanisms and models of somatic cell reprogramming,” Nature Reviews Genetics, vol. 14, no. 6, pp. 427–439, 2013. View at Publisher · View at Google Scholar · View at Scopus
  130. R. P. Koche, Z. D. Smith, M. Adli et al., “Reprogramming factor expression initiates widespread targeted chromatin remodeling,” Cell Stem Cell, vol. 8, no. 1, pp. 96–105, 2011. View at Publisher · View at Google Scholar · View at Scopus
  131. N. Maherali, R. Sridharan, W. Xie et al., “Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution,” Cell Stem Cell, vol. 1, no. 1, pp. 55–70, 2007. View at Publisher · View at Google Scholar · View at Scopus
  132. M. Wernig, A. Meissner, R. Foreman et al., “In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state,” Nature, vol. 448, no. 7151, pp. 318–324, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. J. M. Polo, E. Anderssen, R. M. Walsh et al., “A molecular roadmap of reprogramming somatic cells into iPS cells,” Cell, vol. 151, no. 7, pp. 1617–1632, 2012. View at Publisher · View at Google Scholar · View at Scopus
  134. A. Soufi, G. Donahue, and K. S. Zaret, “Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome,” Cell, vol. 151, no. 5, pp. 994–1004, 2012. View at Publisher · View at Google Scholar · View at Scopus
  135. P. C. Taberlay, T. K. Kelly, C.-C. Liu et al., “Polycomb-repressed genes have permissive enhancers that initiate reprogramming,” Cell, vol. 147, no. 6, pp. 1283–1294, 2011. View at Publisher · View at Google Scholar · View at Scopus
  136. B. Wen, H. Wu, Y. Shinkai, R. A. Irizarry, and A. P. Feinberg, “Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells,” Nature Genetics, vol. 41, no. 2, pp. 246–250, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. R. M. Kohli and Y. Zhang, “TET enzymes, TDG and the dynamics of DNA demethylation,” Nature, vol. 502, no. 7472, pp. 472–479, 2013. View at Publisher · View at Google Scholar · View at Scopus
  138. V. R. Ramirez-Carrozzi, D. Braas, D. M. Bhatt et al., “A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling,” Cell, vol. 138, no. 1, pp. 114–128, 2009. View at Publisher · View at Google Scholar · View at Scopus
  139. K. Kim, A. Doi, B. Wen et al., “Epigenetic memory in induced pluripotent stem cells,” Nature, vol. 467, no. 7313, pp. 285–290, 2010. View at Publisher · View at Google Scholar · View at Scopus
  140. P. L. De Jager, G. Srivastava, K. Lunnon et al., “Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci,” Nature Neuroscience, vol. 17, pp. 1156–1163, 2014. View at Publisher · View at Google Scholar · View at Scopus
  141. K. Lunnon, R. Smith, E. Hannon et al., “Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease,” Nature Neuroscience, vol. 17, pp. 1164–1170, 2014. View at Publisher · View at Google Scholar · View at Scopus
  142. IPDGC and WTCCC2, “A two-stage meta-analysis identifies several new loci for Parkinson's disease,” PLoS Genetics, vol. 7, Article ID e1002142, 2011. View at Google Scholar
  143. E. Masliah, W. Dumaop, D. Galasko, and P. Desplats, “Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes,” Epigenetics, vol. 8, no. 10, pp. 1030–1038, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. J.-F. Poulin, J. Zou, J. Drouin-Ouellet, K.-Y. A. Kim, F. Cicchetti, and R. B. Awatramani, “Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling,” Cell Reports, vol. 9, no. 3, pp. 930–943, 2014. View at Publisher · View at Google Scholar · View at Scopus
  145. E. Gjoneska, A. R. Pfenning, H. Mathys et al., “Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease,” Nature, vol. 518, no. 7539, pp. 365–369, 2015. View at Publisher · View at Google Scholar
  146. E. M. Blalock, H. M. Buechel, J. Popovic, J. W. Geddes, and P. W. Landfield, “Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease,” Journal of Chemical Neuroanatomy, vol. 42, no. 2, pp. 118–126, 2011. View at Publisher · View at Google Scholar · View at Scopus
  147. H. J. van Heesbeen, S. Mesman, J. V. Veenvliet, and M. P. Smidt, “Epigenetic mechanisms in the development and maintenance of dopaminergic neurons,” Development, vol. 140, no. 6, pp. 1159–1169, 2013. View at Publisher · View at Google Scholar · View at Scopus
  148. R. Roessler, S. A. Smallwood, J. V. Veenvliet et al., “Detailed analysis of the genetic and epigenetic signatures of iPSCs-derived mesodiencephalic dopaminergic neurons,” Stem Cell Reports, vol. 2, no. 4, pp. 520–533, 2014. View at Publisher · View at Google Scholar · View at Scopus
  149. C. A. Ross and S. S. Akimov, “Human-induced pluripotent stem cells: potential for neurodegenerative diseases,” Human Molecular Genetics, vol. 23, no. 1, pp. R17–R26, 2014. View at Publisher · View at Google Scholar · View at Scopus
  150. S. J. Chamberlain, P.-F. Chen, K. Y. Ng et al., “Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 41, pp. 17668–17673, 2010. View at Publisher · View at Google Scholar · View at Scopus
  151. Y. Chan, E. T. Lim, N. Sandholm et al., “An excess of risk-increasing low-frequency variants can be a signal of polygenic inheritance in complex diseases,” The American Journal of Human Genetics, vol. 94, no. 3, pp. 437–452, 2014. View at Publisher · View at Google Scholar · View at Scopus
  152. V. Escott-Price, M. A. Nalls, H. R. Morris et al., “Polygenic risk of Parkinson disease is correlated with disease age at onset,” Annals of Neurology, vol. 77, no. 4, pp. 582–591, 2015. View at Publisher · View at Google Scholar
  153. H. Martiskainen, S. Helisalmi, J. Viswanathan et al., “Effects of Alzheimer's disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach,” Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 565–573, 2015. View at Publisher · View at Google Scholar · View at Scopus
  154. R. Torrent, F. de Angelis Rigotti, P. Dell'Era, M. Memo, A. Raya, and A. Consiglio, “Using iPS cells toward the understanding of Parkinson's disease,” Journal of Clinical Medicine, vol. 4, no. 4, pp. 548–566, 2015. View at Publisher · View at Google Scholar
  155. G. Ambrosi, C. Ghezzi, S. Sepe et al., “Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease,” Biochimica et Biophysica Acta, vol. 1842, no. 9, pp. 1385–1394, 2014. View at Publisher · View at Google Scholar · View at Scopus
  156. M. Ramamoorthy, P. Sykora, M. Scheibye-Knudsen et al., “Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype,” Free Radical Biology and Medicine, vol. 53, no. 6, pp. 1371–1380, 2012. View at Publisher · View at Google Scholar · View at Scopus
  157. E. L. Meaburn, L. C. Schalkwyk, and J. Mill, “Allele-specific methylation in the human genome: implications for genetic studies of complex disease,” Epigenetics, vol. 5, no. 7, pp. 578–582, 2010. View at Publisher · View at Google Scholar · View at Scopus
  158. C. A. Hamm and F. F. Costa, “The impact of epigenomics on future drug design and new therapies,” Drug Discovery Today, vol. 16, no. 13-14, pp. 626–635, 2011. View at Publisher · View at Google Scholar · View at Scopus
  159. S. Ichi, F. F. Costa, J. M. Bischof et al., “Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development,” Journal of Biological Chemistry, vol. 285, no. 47, pp. 36922–36932, 2010. View at Publisher · View at Google Scholar · View at Scopus
  160. N. V. Balmer and M. Leist, “Epigenetics and transcriptomics to detect adverse drug effects in model systems of human development,” Basic and Clinical Pharmacology and Toxicology, vol. 115, no. 1, pp. 59–68, 2014. View at Publisher · View at Google Scholar · View at Scopus
  161. S. W. Bihaqi and N. H. Zawia, “Alzheimer's disease biomarkers and epigenetic intermediates following exposure to Pb in vitro,” Current Alzheimer Research, vol. 9, no. 5, pp. 555–562, 2012. View at Publisher · View at Google Scholar · View at Scopus
  162. J. Wu, M. R. Basha, B. Brock et al., “Alzheimer's Disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD,” Journal of Neuroscience, vol. 28, no. 1, pp. 3–9, 2008. View at Publisher · View at Google Scholar · View at Scopus
  163. P. J. Landrigan, B. Sonawane, R. N. Butler, L. Trasande, R. Callan, and D. Droller, “Early environmental origins of neurodegenerative disease in later life,” Environmental Health Perspectives, vol. 113, no. 9, pp. 1230–1233, 2005. View at Publisher · View at Google Scholar · View at Scopus
  164. N. V. Stiegler, A. K. Krug, F. Matt, and M. Leist, “Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures,” Toxicological Sciences, vol. 121, no. 1, pp. 73–87, 2011. View at Publisher · View at Google Scholar · View at Scopus
  165. A. K. Krug, N. V. Balmer, F. Matt, F. Schönenberger, D. Merhof, and M. Leist, “Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants,” Archives of Toxicology, vol. 87, no. 12, pp. 2215–2231, 2013. View at Publisher · View at Google Scholar · View at Scopus
  166. C. Song, A. Kanthasamy, V. Anantharam, F. Sun, and A. G. Kanthasamy, “Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration,” Molecular Pharmacology, vol. 77, no. 4, pp. 621–632, 2010. View at Publisher · View at Google Scholar · View at Scopus
  167. C. Song, A. Kanthasamy, H. Jin, V. Anantharam, and A. G. Kanthasamy, “Paraquat induces epigenetic changes by promoting histone acetylation in cell culture models of dopaminergic degeneration,” NeuroToxicology, vol. 32, no. 5, pp. 586–595, 2011. View at Publisher · View at Google Scholar · View at Scopus
  168. A. Kanthasamy, H. Jin, V. Anantharam et al., “Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration,” NeuroToxicology, vol. 33, no. 4, pp. 833–837, 2012. View at Publisher · View at Google Scholar · View at Scopus
  169. R. Puttagunta, A. Tedeschi, M. G. Sória et al., “PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system,” Nature Communications, vol. 5, article 3527, 2014. View at Publisher · View at Google Scholar · View at Scopus
  170. J. L. Sterneckert, P. Reinhardt, and H. R. Schöler, “Investigating human disease using stem cell models,” Nature Reviews Genetics, vol. 15, no. 9, pp. 625–639, 2014. View at Publisher · View at Google Scholar · View at Scopus
  171. S. Höing, Y. Rudhard, P. Reinhardt et al., “Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay,” Cell Stem Cell, vol. 11, no. 5, pp. 620–632, 2012. View at Publisher · View at Google Scholar · View at Scopus
  172. Y. M. Yang, S. K. Gupta, K. J. Kim et al., “A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS,” Cell Stem Cell, vol. 12, no. 6, pp. 713–726, 2013. View at Publisher · View at Google Scholar · View at Scopus
  173. W.-N. Zhao, C. Cheng, K. M. Theriault, S. D. Sheridan, L.-H. Tsai, and S. J. Haggarty, “A high-throughput screen for Wnt/beta-catenin signaling pathway modulators in human iPSC-derived neural progenitors,” Journal of Biomolecular Screening, vol. 17, no. 9, pp. 1252–1263, 2012. View at Publisher · View at Google Scholar · View at Scopus
  174. A. Sharma, J. C. Wu, and S. M. Wu, “Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening,” Stem Cell Research and Therapy, vol. 4, article 150, 2013. View at Publisher · View at Google Scholar · View at Scopus
  175. A. M. Hossini, M. Megges, A. Prigione et al., “Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer’s disease donor as a model for investigating AD-associated gene regulatory networks,” BMC Genomics, vol. 16, article 84, 2015. View at Publisher · View at Google Scholar
  176. J. Gräff, D. Rei, J.-S. Guan et al., “An epigenetic blockade of cognitive functions in the neurodegenerating brain,” Nature, vol. 483, no. 7388, pp. 222–226, 2012. View at Publisher · View at Google Scholar · View at Scopus
  177. R. N. Saha and K. Pahan, “HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis,” Cell Death and Differentiation, vol. 13, no. 4, pp. 539–550, 2006. View at Publisher · View at Google Scholar · View at Scopus
  178. Y. Feng, J. Jankovic, and Y. C. Wu, “Epigenetic mechanisms in Parkinson's disease,” Journal of the Neurological Sciences, vol. 349, pp. 3–9, 2015. View at Google Scholar
  179. Z. Konsoula and F. A. Barile, “Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders,” Journal of Pharmacological and Toxicological Methods, vol. 66, no. 3, pp. 215–220, 2012. View at Publisher · View at Google Scholar · View at Scopus
  180. S. K. Pirooznia and F. Elefant, “Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities,” Frontiers in Cellular Neuroscience, vol. 7, article 30, 2013. View at Publisher · View at Google Scholar · View at Scopus
  181. P. Shi, M. A. Scott, B. Ghosh et al., “Synapse microarray identification of small molecules that enhance synaptogenesis,” Nature Communications, vol. 2, article 510, 2011. View at Publisher · View at Google Scholar · View at Scopus
  182. M. Zhu, W.-W. Li, and C.-Z. Lu, “Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+,” CNS Neuroscience and Therapeutics, vol. 20, no. 4, pp. 308–316, 2014. View at Publisher · View at Google Scholar · View at Scopus
  183. I. F. Harrison and D. T. Dexter, “Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?” Pharmacology and Therapeutics, vol. 140, no. 1, pp. 34–52, 2013. View at Publisher · View at Google Scholar · View at Scopus
  184. H. Jin, A. Kanthasamy, D. S. Harischandra et al., “Histone hyperacetylation up-regulates protein kinase Cδ in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease,” Journal of Biological Chemistry, vol. 289, no. 50, pp. 34743–34767, 2014. View at Publisher · View at Google Scholar · View at Scopus
  185. A. A. Johnson, J. Sarthi, S. K. Pirooznia, W. Reube, and F. Elefant, “Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimer's disease model,” Journal of Neuroscience, vol. 33, no. 17, pp. 7535–7547, 2013. View at Publisher · View at Google Scholar · View at Scopus
  186. H. Jia, C. D. Morris, R. M. Williams, J. F. Loring, and E. A. Thomas, “HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 1, pp. E56–E64, 2015. View at Publisher · View at Google Scholar · View at Scopus
  187. S. K. Kidd and J. S. Schneider, “Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease,” Neuroscience, vol. 194, pp. 189–194, 2011. View at Publisher · View at Google Scholar · View at Scopus
  188. G.-S. Peng, G. Li, N.-S. Tzeng et al., “Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia,” Molecular Brain Research, vol. 134, no. 1, pp. 162–169, 2005. View at Publisher · View at Google Scholar · View at Scopus
  189. A. M. Urvalek and L. J. Gudas, “Retinoic acid and histone deacetylases regulate epigenetic changes in embryonic stem cells,” Journal of Biological Chemistry, vol. 289, no. 28, pp. 19519–19530, 2014. View at Publisher · View at Google Scholar · View at Scopus
  190. Y. Wang, X. Wang, R. Li et al., “A DNA methyltransferase inhibitor, 5-Aza-2′-deoxycytidine, exacerbates neurotoxicity and upregulates parkinson's disease-related genes in dopaminergic neurons,” CNS Neuroscience and Therapeutics, vol. 19, no. 3, pp. 183–190, 2013. View at Publisher · View at Google Scholar · View at Scopus
  191. A. P. Nicholas, F. D. Lubin, P. J. Hallett et al., “Striatal histone modifications in models of levodopa-induced dyskinesia,” Journal of Neurochemistry, vol. 106, no. 1, pp. 486–494, 2008. View at Publisher · View at Google Scholar · View at Scopus
  192. S. Darmopil, A. B. Martín, I. R. De Diego, S. Ares, and R. Moratalla, “Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation,” Biological Psychiatry, vol. 66, no. 6, pp. 603–613, 2009. View at Publisher · View at Google Scholar · View at Scopus
  193. M. C. N. Marchetto, B. Winner, and F. H. Gage, “Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases,” Human Molecular Genetics, vol. 19, no. 1, Article ID ddq159, pp. R71–R76, 2010. View at Publisher · View at Google Scholar · View at Scopus
  194. A. Sánchez-Danes, P. Benzoni, M. Memo, P. Dell'Era, A. Raya, and A. Consiglio, “Induced pluripotent stem cell-based studies of Parkinson's disease: challenges and promises,” CNS and Neurological Disorders—Drug Targets, vol. 12, no. 8, pp. 1114–1127, 2013. View at Google Scholar · View at Scopus
  195. K. K.-H. Farh, A. Marson, J. Zhu et al., “Genetic and epigenetic fine mapping of causal autoimmune disease variants,” Nature, vol. 518, pp. 337–343, 2015. View at Publisher · View at Google Scholar · View at Scopus
  196. M. J. Li, L. Y. Wang, Z. Xia, P. C. Sham, and J. Wang, “GWAS3D: detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications,” Nucleic acids research, vol. 41, pp. W150–W158, 2013. View at Publisher · View at Google Scholar · View at Scopus
  197. E. R. Gamazon, J. A. Badner, L. Cheng et al., “Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants,” Molecular Psychiatry, vol. 18, no. 3, pp. 340–346, 2013. View at Publisher · View at Google Scholar · View at Scopus
  198. J. Simón-Sánchez, C. Schulte, J. M. Bras et al., “Genome-wide association study reveals genetic risk underlying Parkinson's disease,” Nature Genetics, vol. 41, no. 12, pp. 1308–1312, 2009. View at Publisher · View at Google Scholar · View at Scopus
  199. J. C. Lambert, C. A. Ibrahim-Verbaas, D. Harold et al., “Meta-analysis of 74, 046 individuals identifies 11 new susceptibility loci for Alzheimer's disease,” Nat Genet, pp. 45–1452, 2013. View at Google Scholar
  200. M. A. Nalls, N. Pankratz, C. M. Lill et al., “Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease,” Nature Genetics, vol. 46, no. 9, pp. 989–993, 2014. View at Publisher · View at Google Scholar
  201. L. A. Hindorff, P. Sethupathy, H. A. Junkins et al., “Potential etiologic and functional implications of genome-wide association loci for human diseases and traits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 23, pp. 9362–9367, 2009. View at Publisher · View at Google Scholar · View at Scopus
  202. J. A. Webster, J. R. Gibbs, J. Clarke et al., “Genetic control of human brain transcript expression in Alzheimer disease,” The American Journal of Human Genetics, vol. 84, no. 4, pp. 445–458, 2009. View at Publisher · View at Google Scholar · View at Scopus
  203. F. Zou, H. S. Chai, C. S. Younkin et al., “Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants,” PLoS Genetics, vol. 8, no. 6, Article ID e1002707, 2012. View at Publisher · View at Google Scholar · View at Scopus
  204. E. Grundberg, E. Meduri, J. K. Sandling et al., “Global analysis of dna methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements,” American Journal of Human Genetics, vol. 93, no. 5, pp. 876–890, 2013. View at Publisher · View at Google Scholar · View at Scopus
  205. M. Kasowski, F. Grubert, C. Heffelfinger et al., “Variation in transcription factor binding among humans,” Science, vol. 328, no. 5975, pp. 232–235, 2010. View at Publisher · View at Google Scholar · View at Scopus
  206. H. Heyn, “A symbiotic liaison between the genetic and epigenetic code,” Frontiers in Genetics, vol. 5, article 113, 2014. View at Publisher · View at Google Scholar · View at Scopus