Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease.
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.
Chen-Plotkin
Alice S
AS
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital/B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA.
Sadri-Vakili
Ghazaleh
G
Yohrling
George J
GJ
Braveman
Melissa W
MW
Benn
Caroline L
CL
Glajch
Kelly E
KE
DiRocco
Derek P
DP
Farrell
Laurie A
LA
Krainc
Dimitri
D
Gines
Silvia
S
MacDonald
Marcy E
ME
Cha
Jang-Ho J
JH
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor