References
Query Results -- Details
MGI Accession ID: MGI:3815357
J Number: J:141086
Other Accession IDs:
Title: Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner.
Authors: Benn CL; Sun T; Sadri-Vakili G; McFarland KN; DiRocco DP; Yohrling GJ; Clark TW; Bouzou B; Cha JH
Journal: J Neurosci
Volume: 28
Issue: 42
Date: 2008 Oct 15
Year: 2008
Pages: 10720-33
Review Status: Peer Reviewed
Abstract:
Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease, a fatal neurodegenerative disorder associated with polyglutamine (polyQ) expansion in the huntingtin (Htt) protein. In this study, we show that mutant Htt alters the normal expression of specific mRNA species at least partly by disrupting the binding activities of many transcription factors which govern the expression of the dysregulated mRNA species. Chromatin immunoprecipitation (ChIP) demonstrates Htt occupation of gene promoters in vivo in a polyQ-dependent manner, and furthermore, ChIP-on-chip and ChIP subcloning reveal that wild-type and mutant Htt exhibit differential genomic distributions. Exon 1 Htt binds DNA directly in the absence of other proteins and alters DNA conformation. PolyQ expansion increases Htt-DNA interactions, with binding to recognition elements of transcription factors whose function is altered in HD. Together, these findings suggest mutant Htt modulates gene expression through abnormal interactions with genomic DNA, altering DNA conformation and transcription factor binding.
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