The Role of MicroRNAs in Human Diseases


PDF - Export to EndNote - PubMed Central XML format - PubMed Central XML format

PMID: 23407304 (PubMed) - PMCID: PMC3558168 - View online: PubReader
Volume 2, Issue 4, October-December , Page 161 to 180
Saturday, September 18, 2010 :Received , Friday, December 17, 2010 :Accepted

  • Corresponding author Ph.D., Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran, P.O. Box: 19615-1177., Tel: +98 21 22432020 Fax: +98 21 22432021 E-mail:Ardekani@avicenna.ac.ir
    - Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR , Tehran, Iran

Abstract: MicroRNAs (miRNAs) are short RNA molecules which bind to target mRNAs, resulting in translational repression and gene silencing and are found in all eukaryotic cells. Approximately 2200 miRNA genes have been reported to exist in the mammalian genome, from which over 1000 belong to the human genome. Many major cellular functions such as development, differentiation, growth, and metabolism are known to be regulated by miRNAs. Proximity to other genes in the genome and their locations in introns of coding genes, noncoding genes and exons have been reported to have a major influence on the level of gene expressions in eukaryotic cells. miRNAs are well conserved in eukaryotic system and are believed to be an essential and evolutionary ancient component of gene regulatory networks. Therefore, in recent years miRNAs have been studied as a likely candidate for involvement in most biologic processes and have been implicated in many human diseases.

 

 


Background :
Since the first draft of human genome was published in February 2001, many new dis-coveries have been made which have eluci-dated the complexity of the human genome and subsequently the human proteome. In the past decade, application of genomics and pro-teomics technologies for early detection of diseases have demonstrated that many types of diseases can be diagnosed at an early stage which would be helpful in initiation of treat-ment protocols at an earlier time point in the clinic. We have previously reported the appli-cation of proteomics technologies for early detection of ovarian cancer (1, 2, 3), prostate cancer (4), lymphatic vascular system (5) and drug-induced cardiac toxicities (6). Other genomics and proteomics technologies have been employed in a variety of other diseases (7, 8) in the past decade.

 



Figure 1. The biosynthesis pathway for miRNAs
Figure 1. The biosynthesis pathway for miRNAs




Figure 2. Coding and non-coding DNA in human genome
Figure 2. Coding and non-coding DNA in human genome




Table 1. miRNAs in reproductive cancers (9)
Table 1. miRNAs in reproductive cancers (9)




Table 2. miRNAs in cancer (9)
Table 2. miRNAs in cancer (9)




Table 3. miRNAs in cancer (9)
Table 3. miRNAs in cancer (9)




Table 4. miRNAs in human diseases
Table 4. miRNAs in human diseases





References :
  1. Petricoin EF, Ardekani AM, Hitt BA, Levine PJ, Fusaro VA, Steinberg SM, et al. Use of proteomic patterns in serum to identify ovarian cancer. The Lancet 2002;359(9306):572-577.
  2. Ardekani AM, Lance A Liotta LA, Petricoin EF. Clinical potential of proteomics in the diagnosis of ovarian cancer. Expert Rev Mol Diagn 2002;2(4): 312-320.
  3. Petricoin III EF, Ornstein DK, Paweletz CP, Ardekani AM, Hackett PS, Hitt BA, et al. Serum proteomic patterns for detection of prostate cancer. J Natl Cancer Inst 2002;94(20):1576-1578.
  4. Leak LV, Petricoin EF, Jones M, Paweletz CP, Ardekani AM, Fusaro VA, et al. Proteomic techno-logies to study disease of the lymphatic vascular system. Ann NY Acad Sci 2002;979:211-228.
  5. Petricoin EF, Rajapaske V, Herman EH, Ardekani AM, Ross S, Johann D, et al. Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotection. Toxicol Pathol 2004;32(Suppl 1):122-130.
  6. Kurian S, Grigoryev Y, Head S, Campbell D, Mondala T, Salomon DR. Applying genomics to organ transplantation medicine in both discovery and validation of biomarkers. Int Immunopharma-col 2007;7(14):1948-1960.
  7. Moslemi Naeini M, Ardekani AM. Noncoding RNAs and Cancer. Avicenna J Med Biotech 2009; 1(2):55-70.
  8. 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 (5):843-854.
  9. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001;294(5543): 853-858.
  10. Sevignani C, Calin GA, Siracusa LD, Croce CM. Mammalian micro RNAs: a small world for fine-tuning gene expression. Mamm Genome 2006;17 (3):189-202.
  11. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000;408: 86-89.
  12. Zhang C. MicroRNAs: role in cardiovascular biol-ogy and disease. Clin Sci 2008;114:699-706.
  13. Mattick JS, Makunin IV. Small regulatory RNAs in mammals. Hum Mol Genet 2005;14(Suppl 1): R121- R132.
  14. Pang KC, Frith MC, Mattick JS. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet 2006;22(1):1-5.
  15. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006;15(Suppl 1):R17-R29.
  16. Hastings ML, Krainer AR. Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001;13 (3):302-309.
  17. Morey C, Avner P. Employment opportunities for non-coding RNAs. FEBS Lett 2004;567(1):27-34.
  18. Bilen J, Nan L, Bonini NM. A new role for micro RNA pathways: modulation of degeneration in-duced by pathogenic human disease proteins. Cell Cycle 2006;5(24):2835-2838.
  19. microRNA.org-http://www.microrna.org/microrna/ searchMirnas.do. Accessed on December 13, 2010.
  20. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 2008;79(4):581-588.
  21. Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005; 11:241-247.
  22. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004;23:4051-4060
  23. Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, et al. Clustering and conserva-tion patterns of human microRNAs. Nucl Acids Res 2005;33(8):2697-2706.
  24. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs down-regulate large numbers of target mRNAs. Nature 2005;433:769-773.
  25. Smalheiser NR, Torvik VI. Mammalian miRNAs derived from genomic repeats. Trends Genet 2005; 21(6):322-326.
  26. Whitelaw E, Martin DI. Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet 2001;27:361-365.
  27. Peaston AE, Evsikov AV, Graber JH, de Vries WN, Holbrook AE, Solter D, et al. Retrotrans-posons regulate host genes in mouse oocytes and preimplantation embryos. Dev Cell 2004;7(4):597-606.
  28. Devor EJ. Primate microRNAs miR-220 and miR- 492 lie within processed pseudogenes. J Hered 2006;97(2):186-190.
  29. Herbert A. The four Rs of RNA-directed evolu-tions. Nat Genet 2004;36:19-25.
  30. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001;409: 860-921.
  31. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science 2001;291(5507):1304-1351.
  32. Szymanski M, Barciszewska MZ, Erdmann VA, Barciszewski J. A new frontier for molecular medi-cine: Noncoding RNAs. Biochimica et Biophys Acta 2005;1756(1):65-75.
  33. Bartel D. MicroRNAs: genomics, biogenesis, mechanism, function. Cell 2004;116(2):281-297.
  34. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucl Acids Res 2008;36(Suppl 1):D154-D158.
  35. AE Erson, EM Petty. MicroRNAs in development and disease. Clin Genet 2008;74(4): 296-306.
  36. Aukerman MJ, Sakai H. Regulation of flowering time and floral organ identity by a microRNA and its APETALA2 like target genes. Plant Cell 2003; 15:2730-2741.
  37. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004;303(5654):83-86.
  38. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T. New microRNAs from mouse and human. RNA 2003;9:175-179.
  39. Berezikov E, Plasterk RH. Camels and zebrafish, viruses and cancer: a microRNA update. Hum Mol Genet 2005;14(Suppl 2):R183-R190.
  40. Bartel, B. MicroRNAs directing siRNA biogenesis. Nat Struct Mol Biol 2005;12(7):569-571.
  41. Zamore PD, Haley B. Ribo-genome: the big world of small RNAs. Science 2005;309(5740):1519-1524.
  42. Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell 2005;122(1):6-7.
  43. Klein ME, Impey S, Goodman RH. Role reversal: the regulation of neuronal gene expression by microRNAs. Curr Opin Neurobiol 2005;15(5): 507-513.
  44. Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 2005;308(5732):833-838.
  45. Naguibneva I, Ameyar-Zazoua M, Polesskaya A, Ait-Si-Ali S, Groisman R, Souidi M, et al. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differen-tiation. Nat Cell Biol 2006;8:278-284.
  46. Hatfield SD, Shcherbata HR, Fischer KA, Naka-hara K, Carthew RW, Ruohola-Baker H. Stem cell division is regulated by the microRNA pathway. Nature 2005;435:974-978.
  47. Mattick JS, Igor V. Makunin. Non-coding RNA. Hum Mol Genet 2006;15(Suppl 1):R17-R29.
  48. McManus MT. MicroRNAs and cancer. Semin Cancer Biol 2003;13(4):253-258.
  49. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism and function. Cell 2004;116(2):281-297.
  50. Szymanski M, Barciszewska MZ, Erdmann VA, Barciszewski J. A new frontier for molecular medi-cine: Noncoding RNAs. Biochimica et Biophysica Acta 2005;1756(1):65-75.
  51. Soifer HS, Rossi JJ, Sætrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther 2007;15:2070-2079.
  52. Li M, Mulle CM, Bharadwaj U, Chow KH, Yao Q, Chen C. MicroRNAs: control and loss of control in human physiology and disease. World J Surg 2009; 33(4):667-684.
  53. Zhang B, Pan X, Cobb GP, Anderson TA. Micro RNAs as oncogenes and tumor suppressors. Dev Biol 2007;302(1):1-12.
  54. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumor suppressor network. Nature 2007;447: 1130-1134.
  55. Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 2007;100:1164-1173.
  56. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S. Role of dicer and drosha for endothelial microRNA expression and angiogenesis. Circ Res 2007;101: 59-68.
  57. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006; 108(9):3068-3071.
  58. Chen Y, Gorski DH. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood 2008;111(3):1217-1226.
  59. Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, et al. MicroRNA-210 modulates endothelial cell re-sponse to hypoxia and inhibits the receptor tyrosine-kinase ligand Ephrin-A3. J Biol Chem 2008;283:15878-15883.
  60. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation and angiogenesis. Cardiovasc Res 2008;79(4):581-588.
  61. Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 1994;94(5):2036-2044.
  62. Murohara T, Witzenbichler B, Spyridopoulos I, Asahara T, Ding B, Sullivan A, et al. Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler Thromb Vasc Biol 1999;19: 1156-1161.
  63. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998;101(4): 731-736.
  64. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 1998;101(11):2567-2578.
  65. Zeiher AM. Endothelial vasodilator dysfunction: pathogenetic link to myocardial ischaemia or epi-phenomenon? Lancet 1996;348(Suppl 1):S10-S12.
  66. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9:1370-1376.
  67. Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, et al. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobil-ization of bone marrow-derived endothelial pro-genitor cells contributes to reendothelialization after arterial injury. Circulation 2003;108:3115-3121.
  68. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimen-tal myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004;110:1933-1939.
  69. Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD, et al. Altered microRNA expression in human heart disease. Physiol Genomics 2007;31: 367-373.
  70. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 2005; 436:214-220.
  71. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, et al. A mammalian microRNA ex-pression atlas based on small RNA library se-quencing. Cell 2007;129(7):1401-1414.
  72. Thum T, Catalucci D, Bauersachs J. MicroRNAs: novel regulators in cardiac development and dis-ease. Cardiovas Res 2008;79:562-570.
  73. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol 2002; 12(9):735-739.
  74. Chen JF, 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- 233.
  75. Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a micro RNA. Science 2007;316(5824):575-579.
  76. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, et al. Dysregulation of cardio-genesis, cardiac conduction, and cell cycle in mice lacking miRNA-1–2. Cell 2007;129(2):303-317.
  77. Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med 2007;13:613-618.
  78. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 2007;13:486-491.
  79. Catalucci D, Latronico MV, Ellingsen O, Condo-relli G. Physiological myocardial hypertrophy: how and why? Front Biosci 2008; 13:312-324.
  80. Zhang C. MicroRNAs: role in cardiovascular biol-ogy and disease. Clin Sci 2008;114:699-706.
  81. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115-126.
  82. Silvestre JS, Mallat Z, Tedgui A, Levy BI. Post-ischaemic neovascularization and inflammation. Cardiovasc Res 2008;78(2):242-249.
  83. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endo-thelial expression of vascular cell adhesion. Proc Natl Acad Sci USA 2008;105(5):1516-1521.
  84. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA 2007;104(5):1604-1609.
  85. Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, et al. Modulation of miR-155 and miR-125b levels following lipopolysac-charide/ TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 2007;179(8):5082-5089.
  86. O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expres-sion of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 2008;205(3):585-594.
  87. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/ microRNA-155 for normal immune function. Science 2007;316((5824):608-611.
  88. Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, et al. microRNA-155 re-gulates the generation of immunoglobulin class-switched plasma cells. Immunity 2007;27(6):847-859.
  89. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004;303(5654):83-86.
  90. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 2008;132:875-886.
  91. Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, et al. MiR-150 controls B cell dif-ferentiation by targeting the transcription factor c-Myb. Cell 2007;131(1):146-159.
  92. Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA 2007;104:7080-7085.
  93. Rosa A, Ballarino M, Sorrentino A, Sthandier O, De Angelis FG, Marchioni M, et al. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc Natl Acad Sci USA 2007;104 (50):19849-19854.
  94. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006;103(33):12481-12486.
  95. Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte func-tion by microRNA-223. Nature 2008;451:1125-1129.
  96. Babak T, Zhang W, Morris Q, Blencowe BJ, Hughes TR. Probing microRNAs with microarrays: tissue specificity and functional inference. RNA 2004;10:1813-1819.
  97. Beuvink I, Kolb FA, Budach W, Garnier A, Lange J, Natt F, et al. A novel microarray approach reveals new tissue-specific signatures of known and predicted mammalian microRNAs. Nucl Acids Res 2007;35(7):e52.
  98. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 2004;5:R13.
  99. Berezikov E, Thuemmler F, van Laake LW, Kondova I, Bontrop R, Cuppen E, et al. Diversity of microRNAs in human and chimpanzee brain. Nat Genet 2006;38:1375-1377.
  100. Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 2004;5:R68.
  101. Nelson PT, Baldwin DA, Kloosterman WP, Kaup-pinen S, Plasterk RH, Mourelatos Z. RAKE and LNA-ISH reveal microRNA expression and local-ization in archival human brain. RNA 2006;12: 187-191.
  102. Singh SK. miRNAs: from neurogeneration to neurodegeneration. Pharmacogenomics 2007;8(8): 971-978.
  103. Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. Regulation of miRNA expression during neural cell specification. Eur J Neurosci 2005;21(6):1469-1477.
  104. Nelson PT, Wang WX, Rajeev BW. MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 2008;18(1):130-138.
  105. Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006;24: 857-864.
  106. Kosik KS, Krichevsky AM. The elegance of the microRNAs: a neuronal perspective. Neuron 2005; 47:779-782.
  107. Ehninger D, Li W, Fox K, Stryker MP, Silva AJ. Reversing neurodevelopmental disorders in adults. Neuron 2008;60(6):950-960.
  108. Chang S, Wen S, Chen D, Jin P. Small regulatory RNAs in neurodevelopmental disorders. Hum Mol Genet 2009;18:R18-R26.
  109. Fields RD, Nelson PG. Activity-dependent de-velopment of the vertebrate nervous system. Int Rev Neurobiol 1992;34:133-214.
  110. Nelson PT, Keller JN. RNA in brain disease: no longer just “the messenger in the middle”. J Neuropathol Exp Neurol 2007;66(6):461-468.
  111. Caudy AA, Myers M, Hannon GJ, Hammond SM. Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev 2002; 16:2491-2496.
  112. Ishizuka A, Siomi MC, Siomi H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev 2002;16: 2497-2508.
  113. Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 2004;7:113-117.
  114. Warren ST, Sherman SL. The fragile X syndrome. In: Scriver, CR, Beaudet AL, Valle D, Childs B, Kinzler KW, Vogelstein B. The Metabolic & Molecular Bases of Inherited Disease. 1st ed. New York: McGraw-Hill Companies; 2001,1257-1290.
  115. Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer, A, et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 1991;252(5009):1097-1102.
  116. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length vari-ation in fragile X syndrome. Cell 1991;65(5):905-914.
  117. Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 1991;252:1711-1714.
  118. Ashley CT Jr, Wilkinson KD, Reines D, Warren ST. FMR1 protein: conserved RNP family domains and selective RNA binding. Science 1993;262:563-566.
  119. Feng Y, Absher D, Eberhart DE, Brown V, Malter HE, Warren ST. FMRP associates with polyribo-somes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this associ-ation. Mol Cell 1997;1(1):109-118.
  120. Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U. Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet 2001;10:329-338.
  121. Li Z, Zhang Y, Ku L, Wilkinson KD, Warren ST, Feng Y. The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucl Acids Res 2001;29(11):2276-2283.
  122. Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM. Fragile X mental retardation protein: nucleocytoplasmic shuttling and associ-ation with somatodendritic ribosomes. J Neurosci 1997;17(5):1539-1547.
  123. Schaeffer C, Bardoni B, Mandel JL, Ehresmann B, Ehresmann C, Moine H. The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif. EMBO J 2001;20:4803-4813.
  124. Darnell JC, Fraser CE, Mostovetsky O, Stefani G, Jones TA, Eddy SR, et al. Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain poly-ribosomes. Genes Dev 2005;19:903-918.
  125. Darnell JC, Jensen KB, Jin P, Brown V, Warren ST, Darnell RB. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 2001;107(4):489-499.
  126. Stefani G, Fraser CE, Darnell JC, Darnell RB. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci 2004;24(33):7272-7276.
  127. 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;23:185-188.
  128. Nan X, Campoy FJ, Bird A. MeCP2 is a trans-criptional repressor with abundant binding sites in genomic chromatin. Cell 1997;88(4):471-481.
  129. Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci 2007;10:1513-1514.
  130. Epstein CJ. Down syndrome (trisomy 21). In: Scriver CR, Beaudet AL, Valle D, Childs B, Kinzler KW, Vogelstein B. The Metabolic & Molecular Bases of Inherited Disease. 1st ed. New York: McGraw-Hill Companies; 2001,1223-1249.
  131. Kuhn DE, Nuovo GJ, Martin MM, Malana GE, Pleister AP, Jiang J, et al. Human chromosome 21-derived miRNAs are overexpressed in down syn-drome brains and hearts. Biochem Biophys Res Commun 2008;370(3):473-477.
  132. Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS, et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 30 untranslated region: a mechanism for functional single nucle-otide polymorphisms related to phenotypes. Am J Hum Genet 2007;81(2):405-413.
  133. Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields puta-tive biomarkers and insights into disease pathways. J Alzheimers Dis 2008;14(1): 27-41.
  134. Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alz-heimer’s disease correlates with increased BACE1/ beta-secretase expression. Proc Natl Acad Sci USA 2008;105(17):6415-6420.
  135. Boissonneault V, Plante I, Rivest, Provost P. Micro RNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-con-verting enzyme 1. J Biol Chem 2009;284:1971-1981.
  136. Hebert SS, Horre K, Nicolai L, Bergmans B, Papa-dopoulou AS, Delacourte A, et al. MicroRNA re-gulation of Alzheimer’s amyloid precursor protein expression. Neurobiol Dis 2009;33(3):422-428.
  137. Weinberg MS, Wood MJA. Short non-coding RNA biology and neurodegenerative disorders: novel disease targets and therapeutics. Hum Mol Genet 2009;18:R27-R39.
  138. Lukiw WJ. Micro RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 2007;18(3):297-300.
  139. Lukiw WJ, Pogue AI. Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. J Inorg Biochem 2007;101(9):1265-1269.
  140. 142.Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci 2005;6: 919-930.
  141. 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(3):438-445.
  142. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 2007;8: R27.
  143. Sullivan PF, Kendler KS, Neale MC. Schizophre-nia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60:1187-1192.
  144. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological impli-cations. Lancet 2003;361(9355):417-419.
  145. Egan MF, Weinberger DR, Lu B. Schizophrenia, III: brain-derived neurotropic factor and genetic risk. Am J Psychiatry 2003;160:1242.
  146. Ashe PC, Berry MD, Boulton AA. Schizophrenia, a neurodegenerative disorder with neurodevelopmen-tal antecedents. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4):691-707.
  147. Sokoloff P, Guillin O, Diaz J, Carroll P, Griffon N. Brain-derived neurotrophic factor controls dopa-mine D3 receptor expression: implications for neurodevelopmental psychiatric disorders. Neuro-tox Res 2002;4(7-8):671-678.
  148. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls dopamine D3 re-ceptor expression and triggers behavioral sensitiza-tion. Nature 2001;411:86-89.
  149. Perkins DO, Jeffries C, Sullivan P. Expanding the ‘central dogma’: the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia. Mol Psychiatry 2005; 10:69-78.
  150. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian micro RNA targets. Cell 2003;115(7):787-798.
  151. Pauley KM, Cha S, Chan EKL. MicroRNA in auto-immunity and autoimmune diseases. J Autoimmun 2009;32(3-4):189-194.
  152. Nakasa T, Shigeru Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M, et al. Expression of micro RNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 2008;58(5):1284-1292.
  153. Stanczyk J, Pedrioli DML, Brentano F, Pernaute OS, Kolling C, Gay RE. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 2008;58(4):1001-1009.
  154. Tili E, Michaille JJ, Costinean S, Croce CM. Micro RNAs, the immune system and rheumatic disease. Nat Clin Pract Rheumatol 2008;4:534-541.
  155. Jacob CO, Lee SK, Strassmann G. Mutational analysis of TNF-alpha gene reveals a regulatory role for thec3'-untranslated region in the genetic predisposition to lupus-like autoimmune disease. J Immunol 1996;156(8):3043-3050.
  156. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, et al. A MicroRNA signa-ture associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353:1793-1801.
  157. Yu D, Tan AHM , Hu X, Athanasopoulos V, Simp-son N, Silva DG, et al. Roquin represses autoim-munity by limiting inducible T-cell co-stimulator messenger RNA. Nature 2007;450:299-303.
  158. Leirisalo-Repo M. Early arthritis and infection. Curr Opin Rheumatol 2005;17(4):433-439.
  159. Callan MF. Epstein–Barr virus, arthritis, and the development of lymphoma in arthritis patients. Curr Opin Rheumatol 2004;16(4):399-405.
  160. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, et al. Host immune system gene targeting by a viral miRNA. Science 2007;317(5836):376-381.
  161. Gottwein E, Mukherjee N, Sachse C, Frenzel C, Majoros WH, Chi JTA, et al. A viral microRNA functions as an orthologue of cellular miR-155. Nature 2007;450:1096-1099.
  162. Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EKL. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 2008;10:R101.
  163. Dai Y, Huang YS, Tang M, Lv TY, Hu CX, Tan YH, et al. Microarray analysis of microRNA ex-pression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 2007;16(12):939-946.
  164. Chen XM. MicroRNA signatures in liver diseases. World J Gastroenterol 2009;15(14):1665-1672.
  165. Berkhout B, Jeang KT. RISCy business: Micro RNAs, pathogenesis, and viruses. J Biol Chem 2007;282:26641-26645.
  166. Jin WB, Wu FL, Kong D, Guo AG. HBV-encoded microRNA candidate and its target. Comput Biol Chem 2007;31(2):124-126.
  167. Ghosh Z, Mallick B, Chakrabarti J. Cellular versus viral microRNAs in host-virus interaction. Nucl Acids Res 2009;37:1035-1048.
  168. Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C, et al. A cellular microRNA mediates antiviral defense in human cells. Science 2005;308(5721):557-560.
  169. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver specific microRNA. Science 2005;309(5740):1577-1581.
  170. Chu AS, Friedman JR. A role for microRNA in cystic liver and kidney diseases. J Clin Invest 2008; 118(11):3585-3587.
  171. McCarthy JJ, Esser KA. MicroRNA-1 and micro RNA-133a expression are decreased during skeletal muscle hypertrophy. J Appl Physiol 2007;102(1): 306-313.
  172. Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, et al. Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci USA 2007;104(43): 17016-17021.
  173. Eisenberg I, Alexander MS, Kunkel LM. miRNAs in normal and diseased skeletal muscle. Cell Mol Med 2009;13(1):2-11.
  174. Zavadil J, Narasimhan M, Blumenberg M, Schnei-der RJ. Transforming growth factor-beta and micro RNA: mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 2007;185(1-3):157-161.
  175. Gu J, Iyer VR. PI3K signaling and miRNA expres-sion during the response of quiescent human fibro-blasts to distinct proliferative stimuli. Genome Biol 2006;7:R42.
  176. Shilo S, Roy S, Khanna S, Sen CK. MicroRNA in cutaneous wound healing: a new paradigm. DNA Cell Biol 2007;26(4):227-37.
  177. Sonkoly E, Wei T, Janson PCJ, Saaf A, Lundeberg L, Linder MT, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS ONE 2007;2(7):e610.
  178. Yi R, O’Carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, et al. Morphogenesis in skin is governed by discrete sets of differentially expres-sed microRNAs. Nat Genet 2006;38:356-362.
  179. Krasna M, Domanovic D, Tomsic A, Svajger U, Jeras M. Platelet gel stimulates proliferation of human dermal fibroblasts in vitro. Acta Dermato-ven Alp Panonica Adriat 2007;16(3):105-110.
  180. Bostjancic E, Glavac D. Importance of microRNAs in skin morphogenesis and diseases. Acta Dermato-ven Alp Panonica Adriat 2008;17(3):95-102.
  181. Lebwohl M. Psoriasis. Lancet 2003;361(9364): 1197-1204.
  182. Lowes MA, Bowcock AM, Krueger JG. Patho-genesis and therapy of psoriasis. Nature 2007; 445:866-873.