Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

• Published in: Neurobiology of disease 2006-05, Vol.22 (2), p.233-241
• Main Authors: Chen-Plotkin, Alice S., Sadri-Vakili, Ghazaleh, Yohrling, George J., Braveman, Melissa W., Benn, Caroline L., Glajch, Kelly E., DiRocco, Derek P., Farrell, Laurie A., Krainc, Dimitri, Gines, Silvia, MacDonald, Marcy E., Cha, Jang-Ho J.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites - genetics; Brain - metabolism; Brain - physiopathology; Brain Chemistry - genetics; Cells, Cultured; Chromatin immunoprecipitation; Down-Regulation - genetics; Gene Expression Regulation - genetics; Gene regulation; Humans; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - physiopathology; Huntington's disease; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nuclear Proteins - genetics; Polyglutamine; Promoter Regions, Genetic - genetics; Protein Binding - genetics; Regulatory Elements, Transcriptional - genetics; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Transcription; Transcription factor; Transcriptional Activation - genetics
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2005.11.001

Huntington's disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine tract within the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis; recent evidence suggests a defect in Sp1-mediated transcription. We used chromatin immunoprecipitation (ChIP) assays followed by real-time PCR to quantify the association of Sp1 with individual genes. We find that, despite normal protein levels and normal to increased overall nuclear binding activity, Sp1 has decreased binding to specific promoters of susceptible genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Genes whose mRNA levels are decreased in HD have abnormal Sp1–DNA binding, whereas genes with unchanged mRNA levels have normal levels of Sp1 association. Moreover, the altered binding seen with Sp1 is not found with another transcription factor, NF-Y. These findings suggest that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes.