Abstract
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.
Original language | English (US) |
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Pages (from-to) | 233-241 |
Number of pages | 9 |
Journal | Neurobiology of Disease |
Volume | 22 |
Issue number | 2 |
DOIs | |
State | Published - May 2006 |
Funding
We would like to thank the Massachusetts General Hospital Alzheimer Disease Research Center for supplying human postmortem brain samples. Supported by NINDS NS38106 (J.-H.J.C.), NS045242 (J.-H.J.C. and D.K.; PI: Hersch), NS32765 (M.E.M.), NS16367 (Huntington's Disease Center Without Walls, M.E.M), Glendorn Foundation (J.-H.J.C.), Hereditary Disease Foundation (G.S.-V.), and the HDSA Coalition for the Cure (J.-H.J.C. and M.E.M.). A.S.C.-P. was a Howard Hughes Medical Institute Medical Student Research Fellow.
Keywords
- Chromatin immunoprecipitation
- Gene regulation
- Huntington's disease
- Polyglutamine
- Transcription
- Transcription factor
ASJC Scopus subject areas
- Neurology