Skip to main content
SpringerLink
Log in

Sp1 Regulates Human Huntingtin Gene Expression

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Huntington’s disease (HD) is a hereditary neurodegenerative disorder resulting from the expansion of a polyglutamine tract in the huntingtin protein. The expansion of cytosine–adenine–guanine repeats results in neuronal loss in the striatum and cortex. Mutant huntingtin (HTT) may cause toxicity via a range of different mechanisms. Recent studies indicate that impairment of wild-type HTT function may also contribute to HD pathogenesis. However, the mechanisms regulating HTT expression have not been well defined. In this study, we cloned 1,795 bp of the 5′ flanking region of the human huntingtin gene (htt) and identified a 106-bp fragment containing the transcription start site as the minimal region necessary for promoter activity. Sequence analysis reveals several putative regulatory elements including Sp1, NF-κB, HIF, CREB, NRSF, P53, YY1, AP1, and STAT in the huntingtin promoter. We found functional Sp1 response elements in the huntingtin promoter region. The expression of Sp1 enhanced huntingtin gene transcription and the inhibition of Sp1-mediated transcriptional activation reduced huntingtin gene expression. These results suggest that Sp1 plays an important role in the regulation of the human huntingtin gene expression at the mRNA and protein levels. Our study suggests that the dysregulation of Sp1-mediated huntingtin transcription, combining with mutant huntingtin’s detrimental effect on other Sp1-mediated downstream gene function, may contribute to the pathogenesis of HD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

HD:

Huntington’s disease

References

  • Alba MM, Guigo R (2004) Comparative analysis of amino acid repeats in rodents and humans. Genome Res 14:549–554

    Article  PubMed  CAS  Google Scholar 

  • Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, Krainc D (2005) Genome-wide expression profiling of human blood reveals biomarkers for Huntington’s disease. Proc Natl Acad Sci USA 102:11023–11028

    Article  PubMed  CAS  Google Scholar 

  • Bouwman P, Gollner H, Elsasser H-P, Eckhoff G, Karis A, Grosveld F, Philipsen S, Suske G (2000) Transcription factor Sp3 is essential for post-natal survival and late tooth development. EMBO J 19:655–661

    Article  PubMed  CAS  Google Scholar 

  • Cai F, Chen B, Zhou W, Zis O, Liu S, Holt RA, Honer WG, Song W (2008) SP1 regulates a human SNAP-25 gene expression. J Neurochem 105:512–523

    Article  PubMed  CAS  Google Scholar 

  • Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S (2001) Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 24:182–188

    Article  PubMed  CAS  Google Scholar 

  • Chan EY, Luthi-Carter R, Strand A, Solano SM, Hanson SA, DeJohn MM, Kooperberg C, Chase KO, DiFiglia M, Young AB, Leavitt BR, Cha JH, Aronin N, Hayden MR, Olson JM (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

    Article  PubMed  CAS  Google Scholar 

  • Chen-Plotkin AS, Sadri-Vakili G, Yohrling GJ, Braveman MW, Benn CL, Glajch KE, DiRocco DP, Farrell LA, Krainc D, Gines S, MacDonald ME, Cha JH (2006) Decreased association of the transcription factor Sp1 with genes downregulated in Huntington’s disease. Neurobiol Dis 22:233–241

    Article  PubMed  CAS  Google Scholar 

  • Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W (2004) Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol 24:865–874

    Article  PubMed  CAS  Google Scholar 

  • Cornett J, Cao F, Wang CE, Ross CA, Bates GP, Li SH, Li XJ (2005) Polyglutamine expansion of huntingtin impairs its nuclear export. Nat Genet 37:198–204

    Article  PubMed  CAS  Google Scholar 

  • Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69

    Article  PubMed  CAS  Google Scholar 

  • DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA et al (1995) Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14:1075–1081

    Article  PubMed  CAS  Google Scholar 

  • Dragatsis I, Levine MS, Zeitlin S (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 26:300–306

    Article  PubMed  CAS  Google Scholar 

  • Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, Mouradian MM, Young AB, Tanese N, Krainc D (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296:2238–2243

    Article  PubMed  CAS  Google Scholar 

  • Dynan WS, Tjian R (1983) Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II. Cell 32:669–680

    Article  PubMed  CAS  Google Scholar 

  • Gafni J, Ellerby LM (2002) Calpain activation in Huntington’s disease. J Neurosci 22:4842–4849

    PubMed  CAS  Google Scholar 

  • Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Bussow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE (2004) A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington’s disease. Mol Cell 15:853–865

    Article  PubMed  CAS  Google Scholar 

  • Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li XJ (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19:2522–2534

    PubMed  CAS  Google Scholar 

  • Hilditch-Maguire P, Trettel F, Passani LA, Auerbach A, Persichetti F, MacDonald ME (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797

    Article  PubMed  CAS  Google Scholar 

  • Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li XJ, Stevens ME, Rosemond E, Roder JC, Phillips AG, Rubin EM, Hersch SM, Hayden MR (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:181–192

    Article  PubMed  CAS  Google Scholar 

  • Huang HP, Chu K, Nemoz-Gaillard E, Elberg D, Tsai MJ (2002) Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol 16:541–551

    Article  PubMed  CAS  Google Scholar 

  • Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F (2002) The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2:831–837

    Article  PubMed  CAS  Google Scholar 

  • Jiang H, Poirier MA, Liang Y, Pei Z, Weiskittel CE, Smith WW, DeFranco DB, Ross CA (2006) Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin. Neurobiol Dis 23:543–551

    Article  PubMed  CAS  Google Scholar 

  • Kegel KB, Meloni AR, Yi Y, Kim YJ, Doyle E, Cuiffo BG, Sapp E, Wang Y, Qin ZH, Chen JD, Nevins JR, Aronin N, DiFiglia M (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

    Article  PubMed  CAS  Google Scholar 

  • Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M (2001) Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington’s disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci USA 98:12784–12789

    Article  PubMed  CAS  Google Scholar 

  • Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E et al (1994) A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401–1406

    Article  PubMed  CAS  Google Scholar 

  • Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep 5:958–963

    Article  PubMed  CAS  Google Scholar 

  • Leavitt BR, Guttman JA, Hodgson JG, Kimel GH, Singaraja R, Vogl AW, Hayden MR (2001) Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am J Hum Genet 68:313–324

    Article  PubMed  CAS  Google Scholar 

  • Letovsky J, Dynan W (1989) Measurement of the binding of transcription factor Sp1 to a single GC box recognition sequence. Nucleic Acids Res 17:2639–2653

    Article  PubMed  CAS  Google Scholar 

  • Li R, Knight JD, Jackson SP, Tjian R, Botchan MR (1991) Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription. Cell 65:493–505

    Article  PubMed  CAS  Google Scholar 

  • Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci 21:8473–8481

    PubMed  CAS  Google Scholar 

  • Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22:1277–1287

    Article  PubMed  CAS  Google Scholar 

  • Liu M, Pleasure SJ, Collins AE, Noebels JL, Naya FJ, Tsai MJ, Lowenstein DH (2000) Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc Natl Acad Sci USA 97:865–870

    Article  PubMed  CAS  Google Scholar 

  • Liu S, Zhang S, Bromley-Brits K, Cai F, Zhou W, Xia K, Mittelholtz J, Song W (2011) Transcriptional regulation of TMP21 by NFAT. Mol Neurodegener 6:21

    Article  PubMed  CAS  Google Scholar 

  • Luo S, Vacher C, Davies JE, Rubinsztein DC (2005) Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol 169:647–656

    Article  PubMed  CAS  Google Scholar 

  • Luthi-Carter R, Strand AD, Hanson SA, Kooperberg C, Schilling G, La Spada AR, Merry DE, Young AB, Ross CA, Borchelt DR, Olson JM (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

    Article  PubMed  CAS  Google Scholar 

  • Marcora E, Gowan K, Lee JE (2003) Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2. Proc Natl Acad Sci USA 100:9578–9583

    Article  PubMed  CAS  Google Scholar 

  • Marin M, Karis A, Visser P, Grosveld F, Philipsen S (1997) Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell 89:619–628

    Article  PubMed  CAS  Google Scholar 

  • McGuire JR, Rong J, Li SH, Li XJ (2006) Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons. J Biol Chem 281:3552–3559

    Article  PubMed  CAS  Google Scholar 

  • Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M (2002) PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington’s disease brains. Hum Mol Genet 11:2547–2558

    Article  PubMed  CAS  Google Scholar 

  • Morton AJ, Faull RL, Edwardson JM (2001) Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 56:111–117

    Article  PubMed  CAS  Google Scholar 

  • Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291:2423–2428

    Article  PubMed  CAS  Google Scholar 

  • Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med 205:2781–2789

    Article  PubMed  CAS  Google Scholar 

  • Qiu Z, Norflus F, Singh B, Swindell MK, Buzescu R, Bejarano M, Chopra R, Zucker B, Benn CL, DiRocco DP, Cha JH, Ferrante RJ, Hersch SM (2006) Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective. J Biol Chem 281:16672–16680

    Article  PubMed  CAS  Google Scholar 

  • Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 85:5733–5737

    Article  PubMed  CAS  Google Scholar 

  • Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, Clementi E, Hackam A, Hayden MR, Li Y, Cooper JK, Ross CA, Govoni S, Vincenz C, Cattaneo E (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci 20:3705–3713

    PubMed  CAS  Google Scholar 

  • Rigamonti D, Bolognini D, Mutti C, Zuccato C, Tartari M, Sola F, Valenza M, Kazantsev AG, Cattaneo E (2007) Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators. J Biol Chem 282:24554–24562

    Article  PubMed  CAS  Google Scholar 

  • Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl:S10–S17

    Article  PubMed  Google Scholar 

  • Rubinsztein DC, Carmichael J (2003) Huntington’s disease: molecular basis of neurodegeneration. Expert Rev Mol Med 5:1–21

    Article  PubMed  Google Scholar 

  • Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66

    Article  PubMed  CAS  Google Scholar 

  • Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE (1999) Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci USA 96:4604–4609

    Article  PubMed  CAS  Google Scholar 

  • Sharp AH, Ross CA (1996) Neurobiology of Huntington’s disease. Neurobiol Dis 3:3–15

    Article  PubMed  CAS  Google Scholar 

  • Sipione S, Rigamonti D, Valenza M, Zuccato C, Conti L, Pritchard J, Kooperberg C, Olson JM, Cattaneo E (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum Mol Genet 11:1953–1965

    Article  PubMed  CAS  Google Scholar 

  • Smith R, Brundin P, Li JY (2005) Synaptic dysfunction in Huntington’s disease: a new perspective. Cell Mol Life Sci 62:1901–1912

    Article  PubMed  CAS  Google Scholar 

  • Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM (2000) The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 97:6763–6768

    Article  PubMed  CAS  Google Scholar 

  • Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, Illes K, Lukacsovich T, Zhu YZ, Cattaneo E, Pandolfi PP, Thompson LM, Marsh JL (2004) SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304:100–104

    Article  PubMed  CAS  Google Scholar 

  • Strand AD, Aragaki AK, Baquet ZC, Hodges A, Cunningham P, Holmans P, Jones KR, Jones L, Kooperberg C, Olson JM (2007) Conservation of regional gene expression in mouse and human brain. PLoS Genet 3:e59

    Article  PubMed  Google Scholar 

  • Sugars KL, Rubinsztein DC (2003) Transcriptional abnormalities in Huntington disease. Trends Genet 19:233–238

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Savanenin A, Reddy PH, Liu YF (2001) Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-d-aspartate receptors via post-synaptic density 95. J Biol Chem 276:24713–24718

    Article  PubMed  CAS  Google Scholar 

  • Sun B, Fan W, Balciunas A, Cooper JK, Bitan G, Steavenson S, Denis PE, Young Y, Adler B, Daugherty L, Manoukian R, Elliott G, Shen W, Talvenheimo J, Teplow DB, Haniu M, Haldankar R, Wypych J, Ross CA, Citron M, Richards WG (2002) Polyglutamine repeat length-dependent proteolysis of huntingtin. Neurobiol Dis 11:111–122

    Article  PubMed  CAS  Google Scholar 

  • The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Google Scholar 

  • Usdin MT, Shelbourne PF, Myers RM, Madison DV (1999) Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet 8:839–846

    Article  PubMed  CAS  Google Scholar 

  • Walling HW, Baldassare JJ, Westfall TC (1998) Molecular aspects of Huntington’s disease. J Neurosci Res 54:301–308

    Article  PubMed  CAS  Google Scholar 

  • Wang R, Zhang M, Zhou W, Ly PT, Cai F, Song W (2011) NF-kappaB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression. J Neurochem 116:1160–1170

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Leavitt BR, van Raamsdonk JM, Dragatsis I, Goldowitz D, MacDonald ME, Hayden MR, Friedlander RM (2006) Huntingtin inhibits caspase-3 activation. EMBO J 25:5896–5906

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35:76–83

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Yili Wu for her technical assistance and helpful comments. This work was supported by the Canadian Institutes of Health Research (CIHR), Jack Brown and Family Alzheimer’s Research Foundation. W. S. is the holder of the Canada Research Chair in Alzheimer’s Disease. R. W. and Y. L were supported by the Chinese Scholarship Council award. P.T.T.L. is supported by a MSFHR Senior Graduate Studentship and Alexander Graham Bell NSERC Senior Graduate Studentship.

Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, Canada, BC V6T 1Z3

    Ruitao Wang, Yawen Luo, Philip T. T. Ly, Fang Cai, Haiyan Zou & Weihong Song

  2. Department of Geriatrics, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China

    Ruitao Wang

  3. Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Weihui Zhou & Weihong Song

Authors
  1. Ruitao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yawen Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip T. T. Ly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weihui Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiyan Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weihong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weihong Song.

Additional information

R. Wang and Y. Luo contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, R., Luo, Y., Ly, P.T.T. et al. Sp1 Regulates Human Huntingtin Gene Expression. J Mol Neurosci 47, 311–321 (2012). https://doi.org/10.1007/s12031-012-9739-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-012-9739-z

Keywords

Search

Navigation