Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease

Human Molecular Genetics

Volumn 25, Issue 16, 2016, Pages 3454-3466

  Lin, Lan ^a   Park, Juw Won ^a   Ramachandran, Shyam ^b   Zhang, Yida ^a   Tseng, Yu Ting ^a   Shen, Shihao ^a   Waldvogel, Henry J ^c   Curtis, Maurice A ^c   M Faull, Richard L ^c   Troncoso, Juan C ^d   Pletnikova, Olga ^d   Ross, Christopher A ^d   Davidson, Beverly L ^b,e   Xing, Yi ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^c UNIVERSITY OF AUCKLAND   (New Zealand)

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATAXIN 7; HUNTINGTIN; TRANSCRIPTOME; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; POLYPYRIMIDINE TRACT BINDING PROTEIN; PTBP1 PROTEIN, HUMAN;

ADULT; ALTERNATIVE RNA SPLICING; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; EXON; FEMALE; FOCAL ADHESION; FOLLOW UP; GENE EXPRESSION; GENE EXPRESSION PROFILING; HUMAN; HUNTINGTON CHOREA; MALE; MIDDLE AGED; MOTOR CORTEX; NERVE CELL; NONHUMAN; OLIGODENDROGLIA; PATHOGENESIS; PRIMARY MOTOR CORTEX; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA SEQUENCE; UPREGULATION; AGED; ANIMAL; AUTOPSY; BIOSYNTHESIS; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION; GENETICS; HIGH THROUGHPUT SEQUENCING; METABOLISM; MOUSE; PATHOLOGY; PATHOPHYSIOLOGY;

ADULT; AGED; ALTERNATIVE SPLICING; ANIMALS; AUTOPSY; FEMALE; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION TO DISEASE; HETEROGENEOUS-NUCLEAR RIBONUCLEOPROTEINS; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; HUNTINGTIN PROTEIN; HUNTINGTON DISEASE; MALE; MICE; MIDDLE AGED; MOTOR CORTEX; POLYPYRIMIDINE TRACT-BINDING PROTEIN; TRANSCRIPTOME;

EID: 85014343987     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddw187     Document Type: Article

References (102)

1. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell, 72, 971-983.
2. Ross, C.A. and Shoulson, I. (2009) Huntington disease: pathogenesis, biomarkers, and approaches to experimental therapeutics. Parkinsonism Relat Disord., 15 Suppl 3, S135-S138.
3. Ross, C.A. and Tabrizi, S.J. (2011) Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol., 10, 83-98.
4. Williams, A.J. and Paulson, H.L. (2008) Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci., 31, 521-528.
5. Guo, Z., Rudow, G., Pletnikova, O., Codispoti, K.E., Orr, B.A., Crain, B.J., Duan, W., Margolis, R.L., Rosenblatt, A., Ross, C.A., et al. (2012) Striatal neuronal loss correlates with clinical motor impairment in Huntington's disease. Mov Disord., 27, 1379-1386.
6. Hodges, A., Strand, A.D., Aragaki, A.K., Kuhn, A., Sengstag, T., Hughes, G., Elliston, L.A., Hartog, C., Goldstein, D.R., Thu, D., et al. (2006) Regional and cellular gene expression changes in human Huntington's disease brain. Hum Mol Genet., 15, 965-977.
7. Thu, D.C., Oorschot, D.E., Tippett, L.J., Nana, A.L., Hogg, V.M., Synek, B.J., Luthi-Carter, R., Waldvogel, H.J. and Faull, R.L. (2010) Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease. Brain, 133, 1094-1110.
8. Unschuld, P.G., Joel, S.E., Pekar, J.J., Reading, S.A., Oishi, K., McEntee, J., Shanahan, M., Bakker, A., Margolis, R.L., Bassett, S.S., et al. (2012) Depressive symptoms in prodromal Huntington's Disease correlate with Stroopinterference related functional connectivity in the ventromedial prefrontal cortex. Psychiatry Res., 203, 166-174.
9. Benn, C.L., Sun, T., Sadri-Vakili, G., McFarland, K.N., DiRocco, D.P., Yohrling, G.J., Clark, T.W., Bouzou, B. and Cha, J.H. (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J. Neurosci., 28, 10720-10733.
10. Kegel, K.B., Meloni, A.R., Yi, Y., Kim, Y.J., Doyle, E., Cuiffo, B.G., Sapp, E., Wang, Y., Qin, Z.H., Chen, J.D., 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.
11. Labbadia, J. and Morimoto, R.I. (2013) Huntington's disease: underlying molecular mechanisms and emerging concepts. Trends Biochem. Sci., 38, 378-385.
12. Augood, S.J., Faull, R.L. and Emson, P.C. (1997) Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease. Ann. Neurol., 42, 215-221.
13. Cha, J.H., Kosinski, C.M., Kerner, J.A., Alsdorf, S.A., Mangiarini, L., Davies, S.W., Penney, J.B., Bates, G.P. and Young, A.B. (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.
14. Emson, P.C., Arregui, A., Clement-Jones, V., Sandberg, B.E. and Rossor, M. (1980) Regional distribution of methionineenkephalin and substance P-like immunoreactivity in normal human brain and in Huntington's disease. Brain Res., 199, 147-160.
15. Young, A.B., Greenamyre, J.T., Hollingsworth, Z., Albin, R., D'Amato, C., Shoulson, I. and Penney, J.B. (1988) NMDA receptor losses in putamen from patients with Huntington's disease. Science, 241, 981-983.
16. Benn, C.L., Landles, C., Li, H., Strand, A.D., Woodman, B., Sathasivam, K., Li, S.H., Ghazi-Noori, S., Hockly, E., Faruque, S.M., 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.
17. Schilling, G., Savonenko, A.V., Klevytska, A., Morton, J.L., Tucker, S.M., Poirier, M., Gale, A., Chan, N., Gonzales, V., Slunt, H.H., et al. (2004) Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Hum. Mol. Genet., 13, 1599-1610.
18. Luthi-Carter, R., Strand, A., Peters, N.L., Solano, S.M., Hollingsworth, Z.R., Menon, A.S., Frey, A.S., Spektor, B.S., Penney, E.B., Schilling, G., et al. (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum. Mol. Genet., 9, 1259-1271.
19. Luthi-Carter, R., Strand, A.D., Hanson, S.A., Kooperberg, C., Schilling, G., La Spada, A.R., Merry, D.E., Young, A.B., Ross, C.A., Borchelt, D.R., et al. (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal contextindependent effects. Hum. Mol. Genet., 11, 1927-1937.
20. Sipione, S., Rigamonti, D., Valenza, M., Zuccato, C., Conti, L., Pritchard, J., Kooperberg, C., Olson, J.M. and Cattaneo, E. (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum. Mol. Genet., 11, 1953-1965.
21. Nucifora, F.C., Jr., Sasaki, M., Peters, M.F., Huang, H., Cooper, J.K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V.L., et al. (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science, 291, 2423-2428.
22. Dunah, A.W., Jeong, H., Griffin, A., Kim, Y.M., Standaert, D.G., Hersch, S.M., Mouradian, M.M., Young, A.B., Tanese, N. and Krainc, D. (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science, 296, 2238-2243.
23. Luthi-Carter, R., Hanson, S.A., Strand, A.D., Bergstrom, D.A., Chun, W., Peters, N.L., Woods, A.M., Chan, E.Y., Kooperberg, C., Krainc, D., 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. Lieberman, A.P., Harmison, G., Strand, A.D., Olson, J.M. and Fischbeck, K.H. (2002) Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum. Mol. Genet., 11, 1967-1976.
25. Thompson, L.M. (2003) An expanded role for wild-type huntingtin in neuronal transcription. Nat. Genet., 35, 13-14.
26. Ross, C.A. and Thompson, L.M. (2006) Transcription meets metabolism in neurodegeneration. Nat. Med., 12, 1239-1241.
27. Cui, L., Jeong, H., Borovecki, F., Parkhurst, C.N., Tanese, N. and Krainc, D. (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 127, 59-69.
28. Chen-Plotkin, A.S., Sadri-Vakili, G., Yohrling, G.J., Braveman, M.W., Benn, C.L., Glajch, K.E., DiRocco, D.P., Farrell, L.A., Krainc, D., Gines, S., et al. (2006) Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease. Neurobiol. Dis., 22, 233-241.
29. Marti, E., Pantano, L., Banez-Coronel, M., Llorens, F., Minones-Moyano, E., Porta, S., Sumoy, L., Ferrer, I. and Estivill, X. (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.
30. Bithell, A., Johnson, R. and Buckley, N.J. (2009) Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease. Biochem. Soc. Trans., 37, 1270-1275.
31. Cha, J.H. (2007) Transcriptional signatures in Huntington's disease. Prog. Neurobiol., 83, 228-248.
32. Thomas, E.A., Coppola, G., Tang, B., Kuhn, A., Kim, S., Geschwind, D.H., Brown, T.B., Luthi-Carter, R. and Ehrlich, M.E. (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.
33. Valor, L.M. (2015) Transcription, epigenetics and ameliorative strategies in Huntington's Disease: a genome-wide perspective. Mol. Neurobiol., 51, 406-423.
34. Oldham, M.C., Langfelder, P. and Horvath, S. (2012) Network methods for describing sample relationships in genomic datasets: application to Huntington's disease. BMC Syst. Biol., 6, 63.
35. Langfelder, P., Cantle, J.P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.H., Ramos, E.M., El-Zein, K., Zhao, Y., et al. (2016) Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice. Nat. Neurosci., 19, 623-633.
36. Jin, J., Cheng, Y., Zhang, Y., Wood, W., Peng, Q., Hutchison, E., Mattson, M.P., Becker, K.G. and Duan, W. (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.
37. Narayanan, M., Huynh, J.L., Wang, K., Yang, X., Yoo, S., McElwee, J., Zhang, B., Zhang, C., Lamb, J.R., Xie, T., et al. (2014) Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Mol. Syst. Biol., 10, 743.
38. Neueder, A. and Bates, G.P. (2014) A common gene expression signature in Huntington's disease patient brain regions. BMC Med. Genomics, 7, 60.
39. Ni, Q., Su, X., Chen, J. and Tian, W. (2015) Prediction of Metabolic Gene Biomarkers for Neurodegenerative Disease by an Integrated Network-Based Approach. Biomed. Res. Int., 2015, 432012.
40. Lee, S.T., Chu, K., Im, W.S., Yoon, H.J., Im, J.Y., Park, J.E., Park, K.H., Jung, K.H., Lee, S.K., Kim, M., et al. (2011) Altered microRNA regulation in Huntington's disease models. Exp. Neurol., 227, 172-179.
41. Soldati, C., Bithell, A., Johnston, C., Wong, K.Y., Stanton, L.W. and Buckley, N.J. (2013) Dysregulation of RESTregulated coding and non-coding RNAs in a cellular model of Huntington's disease. J. Neurochem., 124, 418-430.
42. Packer, A.N., Xing, Y., Harper, S.Q., Jones, L. and Davidson, B.L. (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease. J. Neurosci., 28, 14341-14346.
43. Lee, J.H., Tecedor, L., Chen, Y.H., Monteys, A.M., Sowada, M.J., Thompson, L.M. and Davidson, B.L. (2015) Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron, 85, 303-315.
44. Pan, Q., Shai, O., Lee, L.J., Frey, B.J. and Blencowe, B.J. (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet., 40, 1413-1415.
45. Wang, E.T., Sandberg, R., Luo, S., Khrebtukova, I., Zhang, L., Mayr, C., Kingsmore, S.F., Schroth, G.P. and Burge, C.B. (2008) Alternative isoform regulation in human tissue transcriptomes. Nature, 456, 470-476.
46. Black, D.L. and Grabowski, P.J. (2003) Alternative pre-mRNA splicing and neuronal function. Prog. Mol. Subcell. Biol., 31, 187-216.
47. Mazin, P., Xiong, J., Liu, X., Yan, Z., Zhang, X., Li, M., He, L., Somel, M., Yuan, Y., Phoebe Chen, Y.P., et al. (2013) Widespread splicing changes in human brain development and aging. Mol. Syst. Biol., 9, 633.
48. Wang, Z. and Burge, C.B. (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA, 14, 802-813.
49. Cooper, T.A., Wan, L. and Dreyfuss, G. (2009) RNA and disease. Cell, 136, 777-793.
50. Anthony, K. and Gallo, J.M. (2010) Aberrant RNA processing events in neurological disorders. Brain Res., 1338, 67-77.
51. Osborne, R.J., Lin, X., Welle, S., Sobczak, K., O'Rourke, J.R., Swanson, M.S. and Thornton, C.A. (2009) Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. Hum. Mol. Genet., 18, 1471-1481.
52. Ranum, L.P. and Cooper, T.A. (2006) RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci., 29, 259-277.
53. Li, L.B., Yu, Z., Teng, X. and Bonini, N.M. (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature, 453, 1107-1111.
54. Clinton, S.M., Haroutunian, V., Davis, K.L. and Meador-Woodruff, J.H. (2003) Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am. J. Psychiatry, 160, 1100-1109.
55. Dredge, B.K., Polydorides, A.D. and Darnell, R.B. (2001) The splice of life: alternative splicing and neurological disease. Nat. Rev. Neurosci., 2, 43-50.
56. Licatalosi, D.D. and Darnell, R.B. (2006) Splicing regulation in neurologic disease. Neuron, 52, 93-101.
57. Schwab, C., Arai, T., Hasegawa, M., Yu, S. and McGeer, P.L. (2008) Colocalization of transactivation-responsive DNAbinding protein 43 and huntingtin in inclusions of Huntington disease. J. Neuropathol. Exp. Neurol., 67, 1159-1165.
58. Ratovitski, T., Chighladze, E., Arbez, N., Boronina, T., Herbrich, S., Cole, R.N. and Ross, C.A. (2012) Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle, 11, 2006-2021.
59. Fernandez-Nogales, M., Cabrera, J.R., Santos-Galindo, M., Hoozemans, J.J., Ferrer, I., Rozemuller, A.J., Hernandez, F., Avila, J. and Lucas, J.J. (2014) Huntington's disease is a fourrepeat tauopathy with tau nuclear rods. Nat. Med., 20, 881-885.
60. Sathasivam, K., Neueder, A., Gipson, T.A., Landles, C., Benjamin, A.C., Bondulich, M.K., Smith, D.L., Faull, R.L., Roos, R.A., Howland, D., et al. (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl. Acad. Sci. U S A, 110, 2366-2370.
61. Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R. and Ma'ayan, A. (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics, 14, 128.
62. Shen, S., Park, J.W., Lu, Z.X., Lin, L., Henry, M.D., Wu, Y.N., Zhou, Q. and Xing, Y. (2014) rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc. Natl. Acad. Sci. U S A, 111, E5593-E5601.
63. Zhang, W., Xu, C., Bian, C., Tempel, W., Crombet, L., MacKenzie, F., Min, J., Liu, Z. and Qi, C. (2011) Crystal structure of the Cys2His2-type zinc finger domain of human DPF2. Biochem. Biophys. Res. Commun., 413, 58-61.
64. Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M. and Gustafsson, J.A. (2001) Mechanisms of estrogen action. Physiol. Rev., 81, 1535-1565.
65. Weydt, P., Pineda, V.V., Torrence, A.E., Libby, R.T., Satterfield, T.F., Lazarowski, E.R., Gilbert, M.L., Morton, G.J., Bammler, T.K., Strand, A.D., et al. (2006) Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell. Metab., 4, 349-362.
66. Guo, L., Degenstein, L., Dowling, J., Yu, Q.C., Wollmann, R., Perman, B. and Fuchs, E. (1995) Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell, 81, 233-243.
67. Okumura, M., Yamakawa, H., Ohara, O. and Owaribe, K. (2002) Novel alternative splicings of BPAG1 (bullous pemphigoid antigen 1) including the domain structure closely related to MACF (microtubule actin cross-linking factor). J. Biol. Chem., 277, 6682-6687.
68. Jiang, Y.J., Zhou, C.J., Zhou, Z.R., Wu, M. and Hu, H.Y. (2013) Structural basis for recognition of the third SH3 domain of full-length R85 (R85FL)/ponsin by ataxin-7. FEBS Lett., 587, 2905-2911.
69. Kaltenbach, L.S., Romero, E., Becklin, R.R., Chettier, R., Bell, R., Phansalkar, A., Strand, A., Torcassi, C., Savage, J., Hurlburt, A., et al. (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet., 3, e82.
70. Lebre, A.S., Jamot, L., Takahashi, J., Spassky, N., Leprince, C., Ravise, N., Zander, C., Fujigasaki, H., Kussel-Andermann, P., Duyckaerts, C., et al. (2001) Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions. Hum. Mol. Genet., 10, 1201-1213.
71. Lopes, C., Ribeiro, M., Duarte, A.I., Humbert, S., Saudou, F., Pereira de Almeida, L., Hayden, M. and Rego, A.C. (2014) IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice. Mol. Neurobiol., 49, 1126-1142.
72. Wagner, E.J. and Garcia-Blanco, M.A. (2001) Polypyrimidine tract binding protein antagonizes exon definition. Mol. Cell Biol., 21, 3281-3288.
73. Llorian, M., Schwartz, S., Clark, T.A., Hollander, D., Tan, L.Y., Spellman, R., Gordon, A., Schweitzer, A.C., de la Grange, P., Ast, G., et al. (2010) Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Nat. Struct. Mol. Biol., 17, 1114-1123.
74. Abou-Sleymane, G., Chalmel, F., Helmlinger, D., Lardenois, A., Thibault, C., Weber, C., Merienne, K., Mandel, J.L., Poch, O., Devys, D., et al. (2006) Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program. Hum. Mol. Genet., 15, 691-703.
75. Nguyen, H.P., Metzger, S., Holzmann, C., Koczan, D., Thiesen, H.J., von Horsten, S., Riess, O. and Bonin, M. (2008) Age-dependent gene expression profile and protein expression in a transgenic rat model of Huntington's disease. Proteomics Clin. Appl., 2, 1638-1650.
76. Valor, L.M., Guiretti, D., Lopez-Atalaya, J.P. and Barco, A. (2013) Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease. J. Neurosci., 33, 10471-10482.
77. Kita, H., Carmichael, J., Swartz, J., Muro, S., Wyttenbach, A., Matsubara, K., Rubinsztein, D.C. and Kato, K. (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum. Mol. Genet., 11, 2279-2287.
78. Wyttenbach, A., Swartz, J., Kita, H., Thykjaer, T., Carmichael, J., Bradley, J., Brown, R., Maxwell, M., Schapira, A., Orntoft, T.F., 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.
79. Runne, H., Regulier, E., Kuhn, A., Zala, D., Gokce, O., Perrin, V., Sick, B., Aebischer, P., Deglon, N. and Luthi-Carter, R. (2008) Dysregulation of gene expression in primary neuron models of Huntington's disease shows that polyglutaminerelated effects on the striatal transcriptome may not be dependent on brain circuitry. J. Neurosci., 28, 9723-9731.
80. Hodges, A., Hughes, G., Brooks, S., Elliston, L., Holmans, P., Dunnett, S.B. and Jones, L. (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.
81. Desplats, P.A., Kass, K.E., Gilmartin, T., Stanwood, G.D., Woodward, E.L., Head, S.R., Sutcliffe, J.G. and Thomas, E.A. (2006) Selective deficits in the expression of striatalenriched mRNAs in Huntington's disease. J. Neurochem., 96, 743-757.
82. Kuhn, A., Goldstein, D.R., Hodges, A., Strand, A.D., Sengstag, T., Kooperberg, C., Becanovic, K., Pouladi, M.A., Sathasivam, K., Cha, J.H., 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 wildtype huntingtin dosage. Hum. Mol. Genet., 16, 1845-1861.
83. Bebee, T.W., Park, J.W., Sheridan, K.I., Warzecha, C.C., Cieply, B.W., Rohacek, A.M., Xing, Y. and Carstens, R.P. (2015) The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. Elife, 4
84. Cieply, B., Park, J.W., Nakauka-Ddamba, A., Bebee, T.W., Guo, Y., Shang, X., Lengner, C.J., Xing, Y. and Carstens, R.P. (2016) Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins. Cell Rep., 15, 247-255.
85. Damianov, A., Ying, Y., Lin, C.H., Lee, J.A., Tran, D., Vashisht, A.A., Bahrami-Samani, E., Xing, Y., Martin, K.C., Wohlschlegel, J.A., et al. (2016) Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR. Cell, 165, 606-619.
86. Dittmar, K.A., Jiang, P., Park, J.W., Amirikian, K., Wan, J., Shen, S., Xing, Y. and Carstens, R.P. (2012) Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol. Cell Biol., 32, 1468-1482.
87. Ji, X., Park, J.W., Bahrami-Samani, E., Lin, L., Duncan-Lewis, C., Pherribo, G., Xing, Y. and Liebhaber, S.A. (2016) alphaCP binding to a cytosine-rich subset of polypyrimidine tracts drives a novel pathway of cassette exon splicing in the mammalian transcriptome. Nucleic Acids Res., 44, 2283-2297.
88. Lu, Z.X., Huang, Q., Park, J.W., Shen, S., Lin, L., Tokheim, C.J., Henry, M.D. and Xing, Y. (2015) Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. Mol. Cancer Res., 13, 305-318.
89. Yang, Y., Park, J.W., Bebee, T.W., Warzecha, C.C., Guo, Y., Shang, X., Xing, Y. and Carstens, R.P. (2016) Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during the epithelial to mesenchymal transition. Mol. Cell Biol., 36(11):1704-1719.
90. Culver, B.P., Savas, J.N., Park, S.K., Choi, J.H., Zheng, S., Zeitlin, S.O., Yates, J.R 3rd. and Tanese, N. (2012) Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis. J. Biol. Chem., 287, 21599-21614.
91. Tollervey, J.R., Wang, Z., Hortobagyi, T., Witten, J.T., Zarnack, K., Kayikci, M., Clark, T.A., Schweitzer, A.C., Rot, G., Curk, T., et al. (2011) Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res., 21, 1572-1582.
92. Macosko, E.Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A.R., Kamitaki, N., Martersteck, E.M., et al. (2015) Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell, 161, 1202-1214.
93. Labadorf, A., Hoss, A.G., Lagomarsino, V., Latourelle, J.C., Hadzi, T.C., Bregu, J., MacDonald, M.E., Gusella, J.F., Chen, J.F., Akbarian, S., et al. (2015) RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression. PLoS One, 10, e0143563.
94. Rozen, S. and Skaletsky, H. (2000) Primer3 on theWWWfor general users and for biologist programmers. Methods Mol. Biol., 132, 365-386.
95. Hoaglin, D.C., Iglewicz, B. and Tukey, J.W. (1986) Performance of Some Resistant Rules for Outlier Labeling. J. Amer. Statist. Assoc., 81, 991-999.
96. Trapnell, C., Williams, B.A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M.J., Salzberg, S.L., Wold, B.J. and Pachter, L. (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol., 28, 511-515.
97. Cahoy, J.D., Emery, B., Kaushal, A., Foo, L.C., Zamanian, J.L., Christopherson, K.S., Xing, Y., Lubischer, J.L., Krieg, P.A., Krupenko, S.A., et al. (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci., 28, 264-278.
98. Kuhn, A., Thu, D., Waldvogel, H.J., Faull, R.L. and Luthi-Carter, R. (2011) Population-specific expression analysis (PSEA) reveals molecular changes in diseased brain. Nat. Methods, 8, 945-947.
99. Park, J.W., Jung, S., Rouchka, E.C., Tseng, Y.T. and Xing, Y. (2016) rMAPS: RNA map analysis and plotting server for alternative exon regulation. Nucleic Acids Res., pii: gkw410
100. Koressaar, T. and Remm, M. (2007) Enhancements andmodifications of primer design program Primer3. Bioinformatics, 23, 1289-1291.
101. Untergasser, A., Cutcutache, I., Koressaar, T., Ye, J., Faircloth, B.C., Remm, M. and Rozen, S.G. (2012) Primer3-new capabilities and interfaces. Nucleic Acids Res., 40, e115.
102. Lu, Z.X., Jiang, P., Cai, J.J. and Xing, Y. (2011) Context-dependent robustness to 5' splice site polymorphisms in human populations. Hum. Mol. Genet., 20, 1084-1096.