Neurotherapeutics

, Volume 10, Issue 4, pp 621–631 | Cite as

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

  • Miguel A. Varela
  • Thomas C. Roberts
  • Matthew J. A. Wood
Review

Abstract

The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

Keywords

Epigenetics Cancer miRNA ncRNA Neurodegeneration 

Supplementary material

13311_2013_212_MOESM1_ESM.pdf (510 kb)
ESM 1(PDF 510 kb)

References

  1. 1.
    Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429:457–63.PubMedGoogle Scholar
  2. 2.
    Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007;447:425–32.PubMedGoogle Scholar
  3. 3.
    Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development 2005;132:4653–62.PubMedGoogle Scholar
  4. 4.
    Mansour AA, Gafni O, Weinberger L, Zviran A, Ayyash M, Rais Y, et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 2012;488:409–13.PubMedGoogle Scholar
  5. 5.
    Prezioso C, Orlando V. Polycomb proteins in mammalian cell differentiation and plasticity. FEBS Lett 2011;585:2067–77.PubMedGoogle Scholar
  6. 6.
    Bygren LO, Kaati G, Edvinsson S. Longevity determined by paternal ancestors’ nutrition during their slow growth period. Acta Biotheor 2001;49:53–9.PubMedGoogle Scholar
  7. 7.
    Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet 2002;10:682–8.PubMedGoogle Scholar
  8. 8.
    Grossniklaus U, Kelly B, Ferguson-Smith AC, Pembrey M, Lindquist S. Transgenerational epigenetic inheritance: how important is it? Nat Rev Genet 2013;14:228–35.PubMedGoogle Scholar
  9. 9.
    Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci 2008;105:17046–9.PubMedGoogle Scholar
  10. 10.
    Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS. Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 2005;90:4115–8.PubMedGoogle Scholar
  11. 11.
    Sarapas C, Cai G, Bierer LM, Golier JA, Galea S, Ising M, et al. Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks. Dis Markers 2011;30:101–10.PubMedGoogle Scholar
  12. 12.
    Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006;15:R17–R29.PubMedGoogle Scholar
  13. 13.
    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75:843–54.PubMedGoogle Scholar
  14. 14.
    Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403:901–6.PubMedGoogle Scholar
  15. 15.
    Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75:855–62.PubMedGoogle Scholar
  16. 16.
    Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005;6:376–85.PubMedGoogle Scholar
  17. 17.
    Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 2012;13:271–82.PubMedGoogle Scholar
  18. 18.
    Wilson KD, Venkatasubrahmanyam S, Jia F, Sun N, Butte AJ, Wu JC. MicroRNA profiling of human-induced pluripotent stem cells. Stem Cells Dev 2009;18:749–58.PubMedGoogle Scholar
  19. 19.
    Yang C-S, Li Z, Rana TM. microRNAs modulate iPS cell generation. RNA. 2011;17:1451–60.PubMedGoogle Scholar
  20. 20.
    Chen J, Wang G, Lu C, Guo X, Hong W, Kang J, et al. Synergetic cooperation of microRNAs with transcription factors in iPS cell generation. PLoS ONE. 2012;7:e40849.PubMedGoogle Scholar
  21. 21.
    Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol 2009;10:116–25.PubMedGoogle Scholar
  22. 22.
    Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 2008;134:521–33.PubMedGoogle Scholar
  23. 23.
    Judson RL, Babiarz JE, Venere M, Blelloch R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 2009;27:459–61.PubMedGoogle Scholar
  24. 24.
    Bader AG. miR-34 — a microRNA replacement therapy is headed to the clinic. Front Genet 2012;3.Google Scholar
  25. 25.
    Obad S, dos Santos CO, Petri A, Heidenblad M, Broom O, Ruse C, et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet 2011;43:371–8.PubMedGoogle Scholar
  26. 26.
    Nagarajan RP, Costello JF. Molecular epigenetics and genetics in neuro-oncology. Neurother 2009;6:436–46.Google Scholar
  27. 27.
    Gibbons RJ, Higgs DR. Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet 2000;97:204–12.PubMedGoogle Scholar
  28. 28.
    Stöger R, Kajimura TM, Brown WT, Laird CD. Epigenetic variation illustrated by DNA methylation patterns of the Fragile-X Gene FMR1. Hum Mol Genet;6:1791–801.Google Scholar
  29. 29.
    Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 2004;15:12–20.PubMedGoogle Scholar
  30. 30.
    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;23:185–8.PubMedGoogle Scholar
  31. 31.
    Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. Regulation of alternative splicing by histone modifications. Science 2010;327:996–1000.PubMedGoogle Scholar
  32. 32.
    Cowley M, Wood AJ, Böhm S, Schulz R, Oakey RJ. Epigenetic control of alternative mRNA processing at the imprinted Herc3/Nap1l5 locus. Nucleic Acids Res 2012;40:8917–26.PubMedGoogle Scholar
  33. 33.
    Wood AJ, Roberts RG, Monk D, Moore GE, Schulz R, Oakey RJ. A screen for retrotransposed imprinted genes reveals an association between X chromosome homology and maternal germ-line methylation. PLoS Genet 2007;3:e20.PubMedGoogle Scholar
  34. 34.
    Ausió J, Levin DB, De Amorim GV, Bakker S, Macleod PM. Syndromes of disordered chromatin remodeling. Clin Genet 2003;64:83–95.PubMedGoogle Scholar
  35. 35.
    Kosik KS, Krichevsky AM. The elegance of the microRNAs: a neuronal perspective. Neuron 2005;47:779–82.PubMedGoogle Scholar
  36. 36.
    Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 2003;9:1274–81.PubMedGoogle Scholar
  37. 37.
    Fiore R, Khudayberdiev S, Saba R, Schratt G. MicroRNA function in the nervous system. Prog Mol Biol Transl Sci 2011;102:47–100.PubMedGoogle Scholar
  38. 38.
    Saito Y, Saito H. MicroRNAs in cancers and neurodegenerative disorders. Front Genet 2012;3:194.PubMedGoogle Scholar
  39. 39.
    Lee S-T, Chu K, Im W-S, Yoon H-J, Im J-Y, Park J-E, et al. Altered microRNA regulation in Huntington’s disease models. Exp Neurol 2001;227:172–9.Google Scholar
  40. 40.
    Mouradian MM. MicroRNAs in Parkinson’s disease. Neurobiol Dis 2012;46:279–84.PubMedGoogle Scholar
  41. 41.
    Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K, Baumgart J, et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 2012;15:827–35.PubMedGoogle Scholar
  42. 42.
    Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Curry WT, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470–6.PubMedGoogle Scholar
  43. 43.
    Siegel SR, Mackenzie J, Chaplin G, Jablonski NG, Griffiths L. Circulating microRNAs involved in multiple sclerosis. Mol Biol Rep 2012;39:6219–25.PubMedGoogle Scholar
  44. 44.
    Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008;18:997–1006.PubMedGoogle Scholar
  45. 45.
    Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci USA 2011;108:3713–8.PubMedGoogle Scholar
  46. 46.
    Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 2008;26:462–9.PubMedGoogle Scholar
  47. 47.
    Kim D-J, Linnstaedt S, Palma J, Park JC, Ntrivalas E, Kwak-Kim JYH, et al. Plasma components affect accuracy of circulating cancer-related microRNA quantitation. J Mol Diagn 2012;14:71–80.PubMedGoogle Scholar
  48. 48.
    Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, et al. A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 2011;118:449–57.PubMedGoogle Scholar
  49. 49.
    Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009;11:1487–95.PubMedGoogle Scholar
  50. 50.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, et al. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 2008;68:9125–30.PubMedGoogle Scholar
  51. 51.
    Venkataraman S, Alimova I, Fan R, Harris P, Foreman N, Vibhakar R. MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence. PloS One 2010;5:e10748.PubMedGoogle Scholar
  52. 52.
    Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer 2011;10:99.PubMedGoogle Scholar
  53. 53.
    Kopp F, Oak PS, Wagner E, Roidl A. miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression. PloS One 2012;7:e50469.PubMedGoogle Scholar
  54. 54.
    He X, Dong Y, Wu CW, Zhao Z, Ng SSM, Chan FKL, et al. MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med 2012;18:1491–8.Google Scholar
  55. 55.
    Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 2007;104:15805–10.PubMedGoogle Scholar
  56. 56.
    Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CEA, Callegari E, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 2009;113:6411–8.PubMedGoogle Scholar
  57. 57.
    Lee J-Y, Jeong W, Lim W, Lim C-H, Bae S-M, Kim J, et al. Hypermethylation and post-transcriptional regulation of DNA methyltransferases in the ovarian carcinomas of the laying hen. PloS One 2013;8:e61658.PubMedGoogle Scholar
  58. 58.
    Pandi G, Nakka VP, Dharap A, Roopra A, Vemuganti R. MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage. PloS One 2013;8:e58039.PubMedGoogle Scholar
  59. 59.
    Qi L, Hongjuan H, Ning G, Zhengbin H, Yanjiang X, Tiebo Z, et al. miR-370 is stage-specifically expressed during mouse embryonic development and regulates Dnmt3a. FEBS Lett. 2013;587:775–81.PubMedGoogle Scholar
  60. 60.
    Weng Z, Wang D, Zhao W, Song M, You F, Yang L, et al. microRNA-450a targets DNA methyltransferase 3a in hepatocellular carcinoma. Exp Ther Med 2011;2:951–5.PubMedGoogle Scholar
  61. 61.
    Duursma AM, Kedde M, Schrier M, le Sage C, Agami R. miR-148 targets human DNMT3b protein coding region. RNA 2008;14:872–7.PubMedGoogle Scholar
  62. 62.
    Wu Y, Crawford M, Mao Y, Lee RJ, Davis IC, Elton TS, et al. Therapeutic delivery of MicroRNA-29b by cationic lipoplexes for lung cancer. Mol Ther Nucleic Acids 2013;2:e84.PubMedGoogle Scholar
  63. 63.
    Cai K, Wan Y, Sun G, Shi L, Bao X, Wang Z. Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells. Oncol Rep 2012;28:2101–6.PubMedGoogle Scholar
  64. 64.
    Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TFE, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 2008;112:4202–12.PubMedGoogle Scholar
  65. 65.
    Varambally S, Cao Q, Mani R-S, Shankar S, Wang X, Ateeq B, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008;322:1695–9.PubMedGoogle Scholar
  66. 66.
    Friedman JM, Liang G, Liu C-C, Wolff EM, Tsai YC, Ye W, et al. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 2009;69:2623–9.PubMedGoogle Scholar
  67. 67.
    Yu L, Lu J, Zhang B, Liu X, Wang L, Li S-Y, et al. miR-26a inhibits invasion and metastasis of nasopharyngeal cancer by targeting EZH2. Oncol Lett 2013;5:1223–8.PubMedGoogle Scholar
  68. 68.
    Sakurai T, Bilim VN, Ugolkov AV, Yuuki K, Tsukigi M, Motoyama T, et al. The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells. Biochem Biophys Res Commun 2012;422:607–14.PubMedGoogle Scholar
  69. 69.
    Zhang H, Zhang H, Zhao M, Lv Z, Zhang X, Qin X, et al. MiR-138 inhibits tumor growth through repression of EZH2 in non-small cell lung cancer. Cell Physiol Biochem 2013;31:56–65.PubMedGoogle Scholar
  70. 70.
    Zheng F, Liao Y-J, Cai M-Y, Liu Y-H, Liu T-H, Chen S-P, et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 2012;61:278–89.PubMedGoogle Scholar
  71. 71.
    Juan AH, Kumar RM, Marx JG, Young RA, Sartorelli V. Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol Cell 2009;36:61–74.PubMedGoogle Scholar
  72. 72.
    Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, et al. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 2009;28:1714–24.PubMedGoogle Scholar
  73. 73.
    Nohata N, Hanazawa T, Kinoshita T, Inamine A, Kikkawa N, Itesako T, et al. Tumour-suppressive microRNA-874 contributes to cell proliferation through targeting of histone deacetylase 1 in head and neck squamous cell carcinoma. Br J Cancer 2013;108:1648–58.PubMedGoogle Scholar
  74. 74.
    Chen J-F, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 2006;38:228–33.PubMedGoogle Scholar
  75. 75.
    Sandhu SK, Volinia S, Costinean S, Galasso M, Neinast R, Santhanam R, et al. miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model. Proc Natl Acad Sci USA 2012;109:20047–52.PubMedGoogle Scholar
  76. 76.
    Padi SKR, Zhang Q, Rustum YM, Morrison C, Guo B. MicroRNA-627 mediates the epigenetic mechanisms of Vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology 2013;145:437-46PubMedGoogle Scholar
  77. 77.
    Du Z-M, Hu L-F, Wang H-Y, Yan L-X, Zeng Y-X, Shao J-Y, et al. Upregulation of MiR-155 in nasopharyngeal carcinoma is partly driven by LMP1 and LMP2A and downregulates a negative prognostic marker JMJD1A. PloS One 2011;6:e19137.PubMedGoogle Scholar
  78. 78.
    Mann J, Chu DCK, Maxwell A, Oakley F, Zhu N-L, Tsukamoto H, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010;138:705–714.PubMedGoogle Scholar
  79. 79.
    Han K, Gennarino VA, Lee Y, Pang K, Hashimoto-Torii K, Choufani S, et al. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev 2013;27:485–90.PubMedGoogle Scholar
  80. 80.
    Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, et al. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 2008;14:369–81.PubMedGoogle Scholar
  81. 81.
    Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MTS, et al. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal tumorigenesis. Oncogene 2013; doi:10.1038/onc.2012.526.Google Scholar
  82. 82.
    Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 2010;189:127–41.PubMedGoogle Scholar
  83. 83.
    Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell 2008;29:525–31.PubMedGoogle Scholar
  84. 84.
    Johnson R, Zuccato C, Belyaev ND, Guest DJ, Cattaneo E, Buckley NJ. A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol Dis 2008;29:438–45.PubMedGoogle Scholar
  85. 85.
    Tan H, Xu Z, Jin P. Role of noncoding RNAs in trinucleotide repeat neurodegenerative disorders. Exp Neurol 2012;235:469–75.PubMedGoogle Scholar
  86. 86.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003;35:76–83.PubMedGoogle Scholar
  87. 87.
    Noh K-M, Hwang J-Y, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, et al. Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci 2012;109:E962–E971.PubMedGoogle Scholar
  88. 88.
    Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL. The bi-functional microRNA miR-9/miR-9* regulates REST and CoREST and is down-regulated in Huntington’s Disease. J Neurosci 2008; 28:14341–6.PubMedGoogle Scholar
  89. 89.
    Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF. RNA regulation of epigenetic processes. BioEssays 2009;31:51–9.PubMedGoogle Scholar
  90. 90.
    Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012;30:453–9.PubMedGoogle Scholar
  91. 91.
    Varela MA, Roberts TC, Andaloussi SE, Wood MJ. Natural antisense makes sense for gene-specific activation in Brain. Mol Ther Nucleic Acids 2012;1:e24.PubMedGoogle Scholar
  92. 92.
    Younger ST, Corey DR. Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Res 2011;39:5682–91.PubMedGoogle Scholar
  93. 93.
    Place RF, Li L-C, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci 2008;105:1608–13.PubMedGoogle Scholar
  94. 94.
    Tan Y, Zhang B, Wu T, Skogerbø G, Zhu X, Guo X, et al. Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. BMC Mol Biol 2009;10:12.PubMedGoogle Scholar
  95. 95.
    Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene 2012; 31:4257–65.PubMedGoogle Scholar
  96. 96.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27–36.PubMedGoogle Scholar
  97. 97.
    Friday BB, Anderson SK, Buckner J, Yu C, Giannini C, Geoffroy F, et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro-Oncol 2012;14:215–21.PubMedGoogle Scholar
  98. 98.
    Premkumar DR, Jane EP, Agostino NR, DiDomenico JD, Pollack IF. Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage. Mol Carcinog 2013;52:118–33.PubMedGoogle Scholar
  99. 99.
    Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer 2006;95:S2–S6.Google Scholar
  100. 100.
    Pirooznia SK, Elefant F. Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities. Front Cell Neurosci 2013;7:30.PubMedGoogle Scholar
  101. 101.
    Reynolds MF, Sisk EC, Rasgon NL. Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: a review. Curr Med Chem 2007;14:2799–812.PubMedGoogle Scholar
  102. 102.
    Gray SG. Targeting Huntington’s disease through histone deacetylases. Clin Epigenetics. 2011;2:257–77.PubMedGoogle Scholar
  103. 103.
    Garcia-Manero G. Demethylating agents in myeloid malignancies. Curr Opin Oncol 2008;20:705–10.PubMedGoogle Scholar
  104. 104.
    Etcheverry A, Aubry M, de Tayrac M, Vauleon E, Boniface R, Guenot F, et al. DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics 2010;11:701.PubMedGoogle Scholar
  105. 105.
    Zhu D, Hunter SB, Vertino PM, Van Meir EG. Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1. Cancer Res 2011;71:5859–70.PubMedGoogle Scholar
  106. 106.
    Condorelli F, Gnemmi I, Vallario A, Genazzani AA, Canonico PL. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol 2008;153:657–68.PubMedGoogle Scholar
  107. 107.
    Morris KV, Chan SW-L, Jacobsen SE, Looney DJ. Small interfering rna-induced transcriptional gene silencing in human cells. Science 2004;305:1289–92.PubMedGoogle Scholar
  108. 108.
    Knowling S, Stapleton K, Turner A-MW, Uhlmann E, Lehmann T, Vollmer J, et al. Chemically modified oligonucleotides modulate an epigenetically varied and transient form of transcription silencing of HIV-1 in human cells. Mol Ther Nucleic Acids 2012;1:e16.PubMedGoogle Scholar
  109. 109.
    Turner A-MW, De La Cruz J, Morris KV. Mobilization-competent lentiviral vector-mediated sustained transcriptional modulation of HIV-1 expression. Mol Ther 2009;17:360–8.PubMedGoogle Scholar
  110. 110.
    Castanotto D, Tommasi S, Li M, Li H, Yanow S, Pfeifer GP, et al. Short hairpin RNA-directed cytosine (CpG) methylation of the RASSF1A gene promoter in HeLa cells. Mol Ther 2005;12:179–83.PubMedGoogle Scholar
  111. 111.
    Yamagishi M, Ishida T, Miyake A, Cooper DA, Kelleher AD, Suzuki K, et al. Retroviral delivery of promoter-targeted shRNA induces long-term silencing of HIV-1 transcription. Microbes Infect 2009;11:500–8.PubMedGoogle Scholar
  112. 112.
    Perrone L, Devi TS, Hosoya K-I, Terasaki T, Singh LP. Inhibition of TXNIP expression in vivo blocks early pathologies of diabetic retinopathy. Cell Death Dis 2010;1:e65.PubMedGoogle Scholar
  113. 113.
    Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P, Girnary R, et al. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circ Res 2009;105:604–9.PubMedGoogle Scholar
  114. 114.
    Zhou J, Peng C, Li B, Wang F, Zhou C, Hong D, et al. Transcriptional gene silencing of HPV16 E6/E7 induces growth inhibition via apoptosis in vitro and in vivo. Gynecol Oncol 2012;124:296–302.PubMedGoogle Scholar
  115. 115.
    Conley AB, Jordan IK. Epigenetic regulation of human cis-natural antisense transcripts. Nucleic Acids Res 2012;40:1438–45.PubMedGoogle Scholar
  116. 116.
    Roberts TC, Wood MJA. Therapeutic targeting of non-coding RNAs. Essays Biochem 2013;54:127–45.PubMedGoogle Scholar
  117. 117.
    Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL. MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci USA 2012;109:18962–7.PubMedGoogle Scholar
  118. 118.
    Zhang H, Shykind B, Sun T. Approaches to manipulating microRNAs in neurogenesis. Front Neurosci 2013;6.Google Scholar
  119. 119.
    Gascon E, Gao F-B. Cause or effect: misregulation of microRNA pathways in neurodegeneration. Front Neurosci 2012;6:48.PubMedGoogle Scholar
  120. 120.
    Sun G, Ye P, Murai K, Lang M-F, Li S, Zhang H, et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2011;2:529.PubMedGoogle Scholar
  121. 121.
    Tognini P, Putignano E, Coatti A, Pizzorusso T. Experience-dependent expression of miR-132 regulates ocular dominance plasticity. Nat Neurosci 2011;14:1237–9.PubMedGoogle Scholar
  122. 122.
    Young DD, Connelly CM, Grohmann C, Deiters A. Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc 2010;132:7976–81.PubMedGoogle Scholar
  123. 123.
    Gumireddy K, Young DD, Xiong X, Hogenesch JB, Huang Q, Deiters A. Small-molecule inhibitors of MicroRNA miR-21 function. Angew Chem Int Ed 2008;47:7482–4.Google Scholar
  124. 124.
    Connelly CM, Thomas M, Deiters A. High-throughput luciferase reporter assay for small-molecule inhibitors of microRNA function. J Biomol Screen 2012;17:822–8.PubMedGoogle Scholar
  125. 125.
    Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, et al. Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. Proc Natl Acad Sci 2011;108:4394–9.PubMedGoogle Scholar
  126. 126.
    Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, et al. A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol 2008;26:933–40.PubMedGoogle Scholar
  127. 127.
    Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of microRNAs in vivo with “antagomirs.” Nature 2005;438:685–9.PubMedGoogle Scholar
  128. 128.
    Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010;327:198–201.PubMedGoogle Scholar
  129. 129.
    Mahishi LH, Hart RP, Lynch DR, Ratan RR. miR-886-3p levels are elevated in Friedreich ataxia. J Neurosci 2012;32:9369–73.PubMedGoogle Scholar
  130. 130.
    Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013;368:1685–94.PubMedGoogle Scholar
  131. 131.
    Cheng L-C, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 2009;12:399–408.PubMedGoogle Scholar
  132. 132.
    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005;65:6029–33.PubMedGoogle Scholar
  133. 133.
    Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci 2009;106:3507–12.PubMedGoogle Scholar
  134. 134.
    Wibrand K, Pai B, Siripornmongcolchai T, Bittins M, Berentsen B, Ofte ML, et al. MicroRNA regulation of the synaptic plasticity-related gene Arc. PloS One 2012;7:e41688.PubMedGoogle Scholar
  135. 135.
    Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007;4:721–6.PubMedGoogle Scholar
  136. 136.
    Loya CM, Lu CS, Van Vactor D, Fulga TA. Transgenic microRNA inhibition with spatiotemporal specificity in intact organisms. Nat Methods 2009;6:897–903.PubMedGoogle Scholar
  137. 137.
    Otaegi G, Pollock A, Sun T. An optimized sponge for microRNA miR-9 affects spinal motor neuron development in vivo. Front Neurosci 2012;5:146.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2013

Authors and Affiliations

  • Miguel A. Varela
    • 1
  • Thomas C. Roberts
    • 1
    • 2
  • Matthew J. A. Wood
    • 1
  1. 1.Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
  2. 2.Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA

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