Journal of Molecular Neuroscience

, Volume 47, Issue 2, pp 311–321

Sp1 Regulates Human Huntingtin Gene Expression

  • Ruitao Wang
  • Yawen Luo
  • Philip T. T. Ly
  • Fang Cai
  • Weihui Zhou
  • Haiyan Zou
  • Weihong Song
Article

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.

Keywords

Huntingtin Sp1 Transcription Huntington disease 

Abbreviation

HD

Huntington’s disease

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ruitao Wang
    • 1
    • 2
  • Yawen Luo
    • 1
  • Philip T. T. Ly
    • 1
  • Fang Cai
    • 1
  • Weihui Zhou
    • 3
  • Haiyan Zou
    • 1
  • Weihong Song
    • 1
    • 3
  1. 1.Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in NeuroscienceThe University of British ColumbiaVancouverCanada
  2. 2.Department of Geriatrics, The Second Affiliated HospitalHarbin Medical UniversityHeilongjiangChina
  3. 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 DisordersChildren’s Hospital of Chongqing Medical UniversityChongqingChina

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