title: Sp1 regulates human huntingtin gene expression.
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.
authors.affiliation: 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.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Wang
authors.forename: Yawen
authors.initials: Y
authors.lastname: Luo
authors.forename: Philip T T
authors.initials: PT
authors.lastname: Ly
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zou
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D024363:Transcription Initiation Site / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D016329:Sp1 Transcription Factor