Transcription, Epigenetics and Ameliorative Strategies in Huntington’s Disease: a Genome-Wide Perspective

Molecular Neurobiology

Volumn 51, Issue 1, 2015, Pages 406-423

  Valor, Luis M ^a  

^a MIGUEL HERNÁNDEZ UNIVERSITY   (Spain)

Author keywords

Amelioration; Epigenome; Microarray; Next generation sequencing; Polyglutamine; Transcriptome

Indexed keywords

TRANSCRIPTOME;

ANIMAL; BIOLOGICAL MODEL; GENETIC EPIGENESIS; GENETIC TRANSCRIPTION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; HUMAN; HUNTINGTON DISEASE;

ANIMALS; EPIGENESIS, GENETIC; GENOME-WIDE ASSOCIATION STUDY; HUMANS; HUNTINGTON DISEASE; MODELS, BIOLOGICAL; TRANSCRIPTION, GENETIC; TRANSCRIPTOME;

EID: 84929313294     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-014-8715-8     Document Type: Review

References (200)

1. Bates G, Harper P, Jones L, editors (2004) Huntington’s disease. 3rd ed: Oxford University Press
2. Shang H, Danek A, Landwehrmeyer B, Burgunder JM (2012) Huntington’s disease: new aspects on phenotype and genotype. Parkinsonism Relat Disord 18(Suppl 1):S107–S109
3. Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 90:905–981
4. Augood SJ, Faull RL, Emson PC (1997) Dopamine D1 and D2 receptor gene expression in the striatum in Huntington’s disease. Ann Neurol 42:215–221
5. Emson PC, Arregui A, Clement-Jones V, Sandberg BE, Rossor M (1980) Regional distribution of methionine-enkephalin and substance P-like immunoreactivity in normal human brain and in Huntington’s disease. Brain Res 199:147–160
6. Young AB, Greenamyre JT, Hollingsworth Z, Albin R, D'Amato C et al (1988) NMDA receptor losses in putamen from patients with Huntington’s disease. Science 241:981–983
7. Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L et al (1998) Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proc Natl Acad Sci U S A 95:6480–6485
8. Schilling G, Savonenko AV, Klevytska A, Morton JL, Tucker SM et al (2004) Nuclear-targeting of mutant huntingtin fragments produces Huntington’s disease-like phenotypes in transgenic mice. Hum Mol Genet 13:1599–1610
9. Benn CL, Landles C, Li H, Strand AD, Woodman B et al (2005) Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington’s disease. Hum Mol Genet 14:3065–3078
10. Harris AS, Denovan-Wright EM, Hamilton LC, Robertson HA (2001) Protein kinase C beta II mRNA levels decrease in the striatum and cortex of transgenic Huntington’s disease mice. J Psychiatry Neurosci 26:117–122
11. Hebb AL, Robertson HA, Denovan-Wright EM (2004) Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience 123:967–981
12. Kita H, Carmichael J, Swartz J, Muro S, Wyttenbach A et al (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum Mol Genet 11:2279–2287
13. Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J Neurosci 28:14341–14346
14. Sinha M, Ghose J, Das E, Bhattarcharyya NP (2010) Altered microRNAs in STHdh(Q111)/Hdh(Q111) cells: miR-146a targets TBP. Biochem Biophys Res Commun 396:742–747
15. Wyttenbach A, Swartz J, Kita H, Thykjaer T, Carmichael J et al (2001) Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington’s disease. Hum Mol Genet 10:1829–1845
16. Marti E, Pantano L, Banez-Coronel M, Llorens F, Minones-Moyano E et al (2010) A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucleic Acids Res 38:7219–7235
17. Jin J, Cheng Y, Zhang Y, Wood W, Peng Q et al (2012) Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin. J Neurochem 123:477–490
18. Lee ST, Chu K, Im WS, Yoon HJ, Im JY et al (2011) Altered microRNA regulation in Huntington’s disease models. Exp Neurol 227:172–179
19. Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P et al (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington’s disease. Hum Mol Genet 20:2225–2237
20. Ng CW, Yildirim F, Yap YS, Dalin S, Matthews BJ et al (2013) Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc Natl Acad Sci U S A 110:2354–2359
21. Vashishtha M, Ng CW, Yildirim F, Gipson TA, Kratter IH et al (2013) Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A 110:E3027–E3036
22. Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9:1259–1271
23. Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W et al (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11:1911–1926
24. Luthi-Carter R, Strand AD, Hanson SA, Kooperberg C, Schilling G et al (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum Mol Genet 11:1927–1937
25. Strand AD, Aragaki AK, Shaw D, Bird T, Holton J et al (2005) Gene expression in Huntington’s disease skeletal muscle: a potential biomarker. Hum Mol Genet 14:1863–1876
26. Abou-Sleymane G, Chalmel F, Helmlinger D, Lardenois A, Thibault C et al (2006) Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program. Hum Mol Genet 15:691–703
27. Nguyen HP, Metzger S, Holzmann C, Koczan D, Thiesen HJ et al (2008) Age-dependent gene expression profile and protein expression in a transgenic rat model of Huntington’s disease. Proteomics: Clin Appl 2:1638–1650
28. Valor LM, Guiretti D, Lopez-Atalaya JP, Barco A (2013) Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease. J Neurosci 33:10471–10482
29. Kocerha J, Liu Y, Willoughby D, Chidamparam K, Benito J et al (2013) Longitudinal transcriptomic dysregulation in the peripheral blood of transgenic Huntington’s disease monkeys. BMC Neurosci 14:88
30. Fossale E, Seong IS, Coser KR, Shioda T, Kohane IS et al (2011) Differential effects of the Huntington’s disease CAG mutation in striatum and cerebellum are quantitative not qualitative. Hum Mol Genet 20:4258–4267
31. Sipione S, Rigamonti D, Valenza M, Zuccato C, Conti L et al (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum Mol Genet 11:1953–1965
32. Tagawa K, Marubuchi S, Qi ML, Enokido Y, Tamura T et al (2007) The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. J Neurosci 27:868–880
33. Runne H, Regulier E, Kuhn A, Zala D, Gokce O et al (2008) Dysregulation of gene expression in primary neuron models of Huntington’s disease shows that polyglutamine-related effects on the striatal transcriptome may not be dependent on brain circuitry. J Neurosci 28:9723–9731
34. Apostol BL, Illes K, Pallos J, Bodai L, Wu J et al (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet 15:273–285
35. Liang Y, Jiang H, Ratovitski T, Jie C, Nakamura M et al (2009) ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line. Brain Res 1286:221–229
36. Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T et al (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 15:965–977
37. Desplats PA, Kass KE, Gilmartin T, Stanwood GD, Woodward EL et al (2006) Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J Neurochem 96:743–757
38. Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T et al (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16:1845–1861
39. Hodges A, Hughes G, Brooks S, Elliston L, Holmans P et al (2008) Brain gene expression correlates with changes in behavior in the R6/1 mouse model of Huntington’s disease. Genes Brain Behav 7:288–299
40. Cha JH (2007) Transcriptional signatures in Huntington’s disease. Prog Neurobiol 83:228–248
41. Seredenina T, Luthi-Carter R (2012) What have we learned from gene expression profiles in Huntington’s disease? Neurobiol Dis 45:83–98
42. Gines S, Seong IS, Fossale E, Ivanova E, Trettel F et al (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum Mol Genet 12:497–508
43. Choi YS, Lee B, Cho HY, Reyes IB, Pu XA et al (2009) CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington’s disease. Neurobiol Dis 36:259–268
44. DeMarch Z, Giampa C, Patassini S, Bernardi G, Fusco FR (2008) Beneficial effects of rolipram in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 30:375–387
45. Giampa C, Laurenti D, Anzilotti S, Bernardi G, Menniti FS et al (2010) Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One 5:e13417
46. Valenza M, Cattaneo E (2011) Emerging roles for cholesterol in Huntington’s disease. Trends Neurosci 34:474–486
47. Leoni V, Caccia C (2014) Study of cholesterol metabolism in Huntington’s disease. Biochem Biophys Res Commun
48. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506
49. Diamanti D, Mori E, Incarnato D, Malusa F, Fondelli C et al (2013) Whole gene expression profile in blood reveals multiple pathways deregulation in R6/2 mouse model. Biomark Res 1:28
50. Hu Y, Chopra V, Chopra R, Locascio JJ, Liao Z et al (2011) Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse. Proc Natl Acad Sci U S A 108:17141–17146
51. Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F et al (2005) Genome-wide expression profiling of human blood reveals biomarkers for Huntington’s disease. Proc Natl Acad Sci U S A 102:11023–11028
52. Runne H, Kuhn A, Wild EJ, Pratyaksha W, Kristiansen M et al (2007) Analysis of potential transcriptomic biomarkers for Huntington’s disease in peripheral blood. Proc Natl Acad Sci U S A 104:14424–14429
53. Marchina E, Misasi S, Bozzato A, Ferraboli S, Agosti C, et al. (2014) Gene expression profile in fibroblasts of Huntington’s disease patients and controls. J Neurol Sci 337:42–46
54. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR et al (2007) Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis 27:265–277
55. Strand AD, Baquet ZC, Aragaki AK, Holmans P, Yang L et al (2007) Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 27:11758–11768
56. Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E et al (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc Natl Acad Sci U S A 105:15564–15569
57. Thomas EA, Coppola G, Tang B, Kuhn A, Kim S et al (2011) In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons. Hum Mol Genet 20:1049–1060
58. Calabresi P, Centonze D, Bernardi G (2000) Cellular factors controlling neuronal vulnerability in the brain: a lesson from the striatum. Neurology 55:1249–1255
59. Burke RE, O'Malley K (2013) Axon degeneration in Parkinson’s disease. Exp Neurol 246:72–83
60. Tunez I, Tasset I, Perez-De La Cruz V, Santamaria A (2010) 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington’s disease: past, present and future. Molecules 15:878–916
61. Telenius H, Kremer B, Goldberg YP, Theilmann J, Andrew SE et al (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 6:409–414
62. Lee JM, Zhang J, Su AI, Walker JR, Wiltshire T et al (2010) A novel approach to investigate tissue-specific trinucleotide repeat instability. BMC Syst Biol 4:29
63. Mason AG, Tome S, Simard JP, Libby RT, Bammler TK, et al. (2014) Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum Mol Genet 23:1606–1618
64. Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L et al (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137:60–72
65. Chan EY, Luthi-Carter R, Strand A, Solano SM, Hanson SA et al (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington’s disease. Hum Mol Genet 11:1939–1951
66. Tang B, Becanovic K, Desplats PA, Spencer B, Hill AM et al (2012) Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease. Hum Mol Genet 21:3097–3111
67. Jacobsen JC, Gregory GC, Woda JM, Thompson MN, Coser KR et al (2011) HD CAG-correlated gene expression changes support a simple dominant gain of function. Hum Mol Genet 20:2846–2860
68. Lee JM, Galkina EI, Levantovsky RM, Fossale E, Anne Anderson M et al (2013) Dominant effects of the Huntington’s disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy. Hum Mol Genet 22:3227–3238
69. Kuhn A, Thu D, Waldvogel HJ, Faull RL, Luthi-Carter R (2011) Population-specific expression analysis (PSEA) reveals molecular changes in diseased brain. Nat Methods 8:945–947
70. Lovrecic L, Slavkov I, Dzeroski S, Peterlin B (2010) ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2): a new potential biomarker in Huntington’s disease. J Int Med Res 38:1653–1662
71. Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci 55:101–114
72. Lee JM, Ivanova EV, Seong IS, Cashorali T, Kohane I et al (2007) Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet 3:e135
73. Jakovcevski M, Akbarian S (2012) Epigenetic mechanisms in neurological disease. Nat Med 18:1194–1204
74. Urdinguio RG, Sanchez-Mut JV, Esteller M (2009) Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 8:1056–1072
75. Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13:539–550
76. Valor LM, Guiretti D (2014) What’s wrong with epigenetics in Huntington’s disease? Neuropharmacology 80C:103–114
77. Maciotta S, Meregalli M, Torrente Y (2013) The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 7:265
78. Stroynowska-Czerwinska A, Fiszer A, Krzyzosiak WJ (2014) The panorama of miRNA-mediated mechanisms in mammalian cells. Cell Mol Life Sci
79. Johnson R, Zuccato C, Belyaev ND, Guest DJ, Cattaneo E et al (2008) A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol Dis 29:438–445
80. Banez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L et al (2012) A pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 8:e1002481
81. Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M et al (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35:76–83
82. Marcora E, Kennedy MB (2010) The Huntington’s disease mutation impairs Huntingtin’s role in the transport of NF-kappaB from the synapse to the nucleus. Hum Mol Genet 19:4373–4384
83. Futter M, Diekmann H, Schoenmakers E, Sadiq O, Chatterjee K et al (2009) Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J Med Genet 46:438–446
84. Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ et al (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 97:6763–6768
85. Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J et al (1999) Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 8:1647–1655
86. Kazantsev A, Preisinger E, Dranovsky A, Goldgaber D, Housman D (1999) Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci U S A 96:11404–11409
87. Huang CC, Faber PW, Persichetti F, Mittal V, Vonsattel JP et al (1998) Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet 24:217–233
88. Holbert S, Denghien I, Kiechle T, Rosenblatt A, Wellington C et al (2001) The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 98:1811–1816
89. Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S et al (2005) Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci 25:9932–9939
90. Obrietan K, Hoyt KR (2004) CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 24:791–796
91. Sugars KL, Brown R, Cook LJ, Swartz J, Rubinsztein DC (2004) Decreased cAMP response element-mediated transcription: an early event in exon 1 and full-length cell models of Huntington’s disease that contributes to polyglutamine pathogenesis. J Biol Chem 279:4988–4999
92. Lu B, Palacino J (2013) A novel human embryonic stem cell-derived Huntington’s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration. FASEB J 27:1820–1829
93. Leitman J, Ulrich Hartl F, Lederkremer GZ (2013) Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat Commun 4:2753
94. Tian J, Yan YP, Zhou R, Lou HF, Rong Y, et al. (2013) Soluble N-terminal fragment of mutant Huntingtin protein impairs mitochondrial axonal transport in cultured hippocampal neurons. Neurosci Bull
95. Arrasate M, Finkbeiner S (2012) Protein aggregates in Huntington’s disease. Exp Neurol 238:1–11
96. Yu ZX, Li SH, Nguyen HP, Li XJ (2002) Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice. Hum Mol Genet 11:905–914
97. Tallaksen-Greene SJ, Crouse AB, Hunter JM, Detloff PJ, Albin RL (2005) Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice. Neuroscience 131:843–852
98. Cong SY, Pepers BA, Evert BO, Rubinsztein DC, Roos RA et al (2005) Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Mol Cell Neurosci 30:560–571
99. Choi YJ, Kim SI, Lee JW, Kwon YS, Lee HJ et al (2012) Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic cell death. Mol Cell Neurosci 49:127–137
100. Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG et al (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296:2238–2243
101. Li SH, Cheng AL, Zhou H, Lam S, Rao M et al (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22:1277–1287
102. Sadri-Vakili G, Menon AS, Farrell LA, Keller-McGandy CE, Cantuti-Castelvetri I et al (2006) Huntingtin inclusions do not down-regulate specific genes in the R6/2 Huntington’s disease mouse. Eur J Neurosci 23:3171–3175
103. Benn CL, Sun T, Sadri-Vakili G, McFarland KN, DiRocco DP et al (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci 28:10720–10733
104. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N et al (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69
105. Yamanaka T, Miyazaki H, Oyama F, Kurosawa M, Washizu C et al (2008) Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. EMBO J 27:827–839
106. Godin JD, Poizat G, Hickey MA, Maschat F, Humbert S (2010) Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington’s disease. EMBO J 29:2433–2445
107. Saura CA, Valero J (2011) The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 22:153–169
108. Datta M, Choudhury A, Lahiri A, Bhattacharyya NP (2011) Genome wide gene expression regulation by HIP1 Protein Interactor, HIPPI: prediction and validation. BMC Genomics 12:463
109. Jovicic A, Zaldivar Jolissaint JF, Moser R, Silva Santos Mde F, Luthi-Carter R (2013) MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington’s disease-related mechanisms. PLoS One 8:e54222
110. Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M et al (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J Neurosci 27:6972–6983
111. McFarland KN, Das S, Sun TT, Leyfer D, Xia E et al (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington’s disease. PLoS One 7:e41423
112. Riva L, Koeva M, Yildirim F, Pirhaji L, Dinesh D et al (2012) Poly-glutamine expanded huntingtin dramatically alters the genome wide binding of HSF1. J Huntingtons Dis 1:33–45
113. Lee J, Hwang YJ, Shin JY, Lee WC, Wie J et al (2013) Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca(2+) signaling in Huntington’s disease. Acta Neuropathol 125:727–739
114. Adachi M, Monteggia LM (2014) Decoding transcriptional repressor complexes in the adult central nervous system. Neuropharmacology 80C:45–52
115. Johnson R, Richter N, Jauch R, Gaughwin PM, Zuccato C, et al. (2010) The Human Accelerated Region 1 noncoding RNA is repressed by REST in Huntington’s disease. Physiol Genomics 41:269–274
116. Soldati C, Bithell A, Johnston C, Wong KY, Stanton LW et al (2013) Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington’s disease. J Neurochem 124:418–430
117. Le Fevre AK, Taylor S, Malek NH, Horn D, Carr CW et al (2013) FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am J Med Genet A 161A:3166–3175
118. Hay DG, Sathasivam K, Tobaben S, Stahl B, Marber M et al (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13:1389–1405
119. Labbadia J, Cunliffe H, Weiss A, Katsyuba E, Sathasivam K et al (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest 121:3306–3319
120. Lucas EK, Dougherty SE, McMeekin LJ, Trinh AT, Reid CS et al (2012) Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1alpha. PLoS One 7:e42878
121. Levenson JM, O'Riordan KJ, Brown KD, Trinh MA, Molfese DL et al (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559
122. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756
123. Parkel S, Lopez-Atalaya JP, Barco A (2013) Histone H3 lysine methylation in cognition and intellectual disability disorders. Learn Mem 20:570–579
124. Wang F, Yang Y, Lin X, Wang JQ, Wu YS et al (2013) Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington’s disease. Hum Mol Genet 22:3641–3653
125. Giorgini F, Moller T, Kwan W, Zwilling D, Wacker JL et al (2008) Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J Biol Chem 283:7390–7400
126. Kurdistani SK, Robyr D, Tavazoie S, Grunstein M (2002) Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nat Genet 31:248–254
127. Tauber E, Miller-Fleming L, Mason RP, Kwan W, Clapp J et al (2011) Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity. J Biol Chem 286:410–419
128. Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T et al (2013) HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol 11:e1001717
129. Sando R 3rd, Gounko N, Pieraut S, Liao L, Yates J 3rd et al (2012) HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151:821–834
130. Mielcarek M, Seredenina T, Stokes MP, Osborne GF, Landles C et al (2013) HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo. PLoS One 8:e80849
131. Kegel KB, Meloni AR, Yi Y, Kim YJ, Doyle E et al (2002) Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J Biol Chem 277:7466–7476
132. Ferrante RJ, Ryu H, Kubilus JK, D'Mello S, Sugars KL et al (2004) Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington’s disease. J Neurosci 24:10335–10342
133. Stack EC, Del Signore SJ, Luthi-Carter R, Soh BY, Goldstein DR et al (2007) Modulation of nucleosome dynamics in Huntington’s disease. Hum Mol Genet 16:1164–1175
134. Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE et al (2006) ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington’s disease. Proc Natl Acad Sci U S A 103:19176–19181
135. Gardian G, Browne SE, Choi DK, Klivenyi P, Gregorio J et al (2005) Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease. J Biol Chem 280:556–563
136. Lee J, Hong YK, Jeon GS, Hwang YJ, Kim KY et al (2012) ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington’s disease. Cell Death Differ 19:1109–1116
137. Lee J, Hagerty S, Cormier KA, Kim J, Kung AL et al (2008) Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation. Hum Mol Genet 17:1774–1782
138. Buckley NJ, Johnson R, Zuccato C, Bithell A, Cattaneo E (2010) The role of REST in transcriptional and epigenetic dysregulation in Huntington’s disease. Neurobiol Dis 39:28–39
139. Soldati C, Bithell A, Conforti P, Cattaneo E, Buckley NJ (2011) Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington’s disease. J Neurochem 116:415–425
140. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490–495
141. Martin E, Betuing S, Pages C, Cambon K, Auregan G et al (2011) Mitogen- and stress-activated protein kinase 1-induced neuroprotection in Huntington’s disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet 20:2422–2434
142. Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N et al (2005) p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 47:29–41
143. Jiang M, Wang J, Fu J, Du L, Jeong H et al (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158
144. Illuzzi JL, Vickers CA, Kmiec EB (2011) Modifications of p53 and the DNA damage response in cells expressing mutant form of the protein huntingtin. J Mol Neurosci 45:256–268
145. Brooks CL, Gu W (2011) The impact of acetylation and deacetylation on the p53 pathway. Protein Cell 2:456–462
146. Brochier C, Dennis G, Rivieccio MA, McLaughlin K, Coppola G et al (2013) Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci 33:8621–8632
147. Lee J, Hwang YJ, Boo JH, Han D, Kwon OK et al (2011) Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington’s disease. Cell Death Differ 18:1726–1735
148. Altar CA, Vawter MP, Ginsberg SD (2009) Target identification for CNS diseases by transcriptional profiling. Neuropsychopharmacology 34:18–54
149. Valor LM, Barco A (2012) Hippocampal gene profiling: toward a systems biology of the hippocampus. Hippocampus 22:929–941
150. Zhang Y, Friedlander RM (2011) Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther 18:1139–1149
151. Drouet V, Perrin V, Hassig R, Dufour N, Auregan G et al (2009) Sustained effects of nonallele-specific Huntingtin silencing. Ann Neurol 65:276–285
152. Boudreau RL, McBride JL, Martins I, Shen S, Xing Y et al (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol Ther 17:1053–1063
153. Grondin R, Kaytor MD, Ai Y, Nelson PT, Thakker DR et al (2012) Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135:1197–1209
154. Strehlow AN, Li JZ, Myers RM (2007) Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. Hum Mol Genet 16:391–409
155. Zhang H, Das S, Li QZ, Dragatsis I, Repa J et al (2008) Elucidating a normal function of huntingtin by functional and microarray analysis of huntingtin-null mouse embryonic fibroblasts. BMC Neurosci 9:38
156. Boudreau RL, Spengler RM, Davidson BL (2011) Rational design of therapeutic siRNAs: minimizing off-targeting potential to improve the safety of RNAi therapy for Huntington’s disease. Mol Ther 19:2169–2177
157. Yamamoto A, Cremona ML, Rothman JE (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172:719–731
158. Varma H, Yamamoto A, Sarantos MR, Hughes RE, Stockwell BR (2010) Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway. J Biol Chem 285:37445–37457
159. Morton AJ, Hunt MJ, Hodges AK, Lewis PD, Redfern AJ et al (2005) A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington’s disease. Eur J Neurosci 21:855–870
160. Hockly E, Cordery PM, Woodman B, Mahal A, van Dellen A et al (2002) Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 51:235–242
161. Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A et al (2004) Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J Neurosci 24:2270–2276
162. Nithianantharajah J, Barkus C, Murphy M, Hannan AJ (2008) Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiol Dis 29:490–504
163. van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ (2000) Delaying the onset of Huntington’s in mice. Nature 404:721–722
164. Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7:697–709
165. Benn CL, Luthi-Carter R, Kuhn A, Sadri-Vakili G, Blankson KL et al (2010) Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease. J Neuropathol Exp Neurol 69:817–827
166. Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ et al (2000) Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci U S A 97:12880–12884
167. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z et al (2005) Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120:701–713
168. Lopez-Atalaya JP, Ciccarelli A, Viosca J, Valor LM, Jimenez-Minchan M et al (2011) CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement. EMBO J 30:4287–4298
169. Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930
170. Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30:14708–14718
171. Giampa C, Montagna E, Dato C, Melone MA, Bernardi G et al (2013) Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington’s disease. PLoS One 8:e64037
172. Mugat B, Parmentier ML, Bonneaud N, Chan HY, Maschat F (2008) Protective role of Engrailed in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3601–3616
173. Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A et al (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 23:9418–9427
174. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A et al (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107:7927–7932
175. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840
176. Pang B, Qiao X, Janssen L, Velds A, Groothuis T et al (2013) Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun 4:1908
177. Nagai Y, Fujikake N, Popiel HA, Wada K (2010) Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. Curr Pharm Biotechnol 11:188–197
178. Guertin MJ, Petesch SJ, Zobeck KL, Min IM, Lis JT (2010) Drosophila heat shock system as a general model to investigate transcriptional regulation. Cold Spring Harb Symp Quant Biol 75:1–9
179. Conforti P, Zuccato C, Gaudenzi G, Ieraci A, Camnasio S et al (2013) Binding of the repressor complex REST-mSIN3b by small molecules restores neuronal gene transcription in Huntington’s disease models. J Neurochem 127:22–35
180. Charbord J, Poydenot P, Bonnefond C, Feyeux M, Casagrande F et al (2013) High throughput screening for inhibitors of REST in neural derivatives of human embryonic stem cells reveals a chemical compound that promotes expression of neuronal genes. Stem Cells 31:1816–1828
181. Friedrich B, Euler P, Ziegler R, Kuhn A, Landwehrmeyer BG et al (2012) Comparative analyses of Purkinje cell gene expression profiles reveal shared molecular abnormalities in models of different polyglutamine diseases. Brain Res 1481:37–48
182. Euler P, Friedrich B, Ziegler R, Kuhn A, Lindenberg KS et al (2012) Gene expression analysis on a single cell level in Purkinje cells of Huntington’s disease transgenic mice. Neurosci Lett 517:7–12
183. Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617
184. Valor LM, Viosca J, Lopez-Atalaya JP, Barco A (2013) Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders. Curr Pharm Des 19:5051–5064
185. Osada N, Kosuge Y, Oguchi S, Miyagishi H, Ishige K et al (2012) Protective action of mithramycin against neurodegeneration and impairment of synaptic plasticity in the hippocampal CA1 area after transient global ischemia. Neurochem Int 60:47–54
186. Sleiman SF, Langley BC, Basso M, Berlin J, Xia L et al (2011) Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci 31:6858–6870
187. Paul S, Mahanta S (2014) Association of heat-shock proteins in various neurodegenerative disorders: is it a master key to open the therapeutic door? Mol Cell Biochem 386:45–61
188. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE et al (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337
189. Valor LM, Jancic D, Lujan R, Barco A (2010) Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function. Cell Death Differ 17:1636–1644
190. Borjabad A, Volsky DJ (2012) Common transcriptional signatures in brain tissue from patients with HIV-associated neurocognitive disorders, Alzheimer’s disease, and Multiple Sclerosis. J Neuroimmune Pharmacol 7:914–926
191. Poirel CL, Rahman A, Rodrigues RR, Krishnan A, Addesa JR et al (2013) Reconciling differential gene expression data with molecular interaction networks. Bioinformatics 29:622–629
192. Zucker B, Kama JA, Kuhn A, Thu D, Orlando LR et al (2010) Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease. J Neuropathol Exp Neurol 69:880–895
193. Luthi-Carter R, Apostol BL, Dunah AW, DeJohn MM, Farrell LA et al (2003) Complex alteration of NMDA receptors in transgenic Huntington’s disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins, and phosphorylation. Neurobiol Dis 14:624–636
194. Kotliarova S, Jana NR, Sakamoto N, Kurosawa M, Miyazaki H et al (2005) Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates. J Neurochem 93:641–653
195. Crocker SF, Costain WJ, Robertson HA (2006) DNA microarray analysis of striatal gene expression in symptomatic transgenic Huntington’s mice (R6/2) reveals neuroinflammation and insulin associations. Brain Res 1088:176–186
196. Sadri-Vakili G, Bouzou B, Benn CL, Kim MO, Chawla P et al (2007) Histones associated with downregulated genes are hypo-acetylated in Huntington’s disease models. Hum Mol Genet 16:1293–1306
197. Lorincz MT, Zawistowski VA (2009) Expanded CAG repeats in the murine Huntington’s disease gene increases neuronal differentiation of embryonic and neural stem cells. Mol Cell Neurosci 40:1–13
198. Tang B, Seredenina T, Coppola G, Kuhn A, Geschwind DH et al (2011) Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington’s disease. Neurobiol Dis 42:459–467
199. Feyeux M, Bourgois-Rocha F, Redfern A, Giles P, Lefort N et al (2012) Early transcriptional changes linked to naturally occurring Huntington’s disease mutations in neural derivatives of human embryonic stem cells. Hum Mol Genet 21:3883–3895
200. Ribeiro FM, Devries RA, Hamilton A, Guimaraes IM, Cregan SP, et al. (2014) Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington’s disease. Hum Mol Genet 23:2030–2042