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The Journal of Neuroscience, October 15, 2008, 28(42):10720-10733; doi:10.1523/JNEUROSCI.2126-08.2008

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Neurobiology of Disease
Huntingtin Modulates Transcription, Occupies Gene Promoters In Vivo, and Binds Directly to DNA in a Polyglutamine-Dependent Manner

Caroline L. Benn,¹ Tingting Sun,¹ Ghazaleh Sadri-Vakili,¹ Karen N. McFarland,¹ Derek P. DiRocco,¹ George J. Yohrling,^1,3 Timothy W. Clark,² Bérengère Bouzou,² and Jang-Ho J. Cha¹

¹Department of Neurology and ²Center for Interdisciplinary Informatics, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129-4404, and ³Galleon Pharmaceuticals, Horsham, Pennsylvania 19044

Correspondence should be addressed to Jang-Ho J. Cha, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129-4404. Email: cha{at}helix.mgh.harvard.edu

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.

Key words: transcription factor; chromatin immunoprecipitation; DNA microarrays; polyglutamine; gene expression; DNA conformation

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Received May 7, 2008; revised June 27, 2008; accepted July 3, 2008.

Correspondence should be addressed to Jang-Ho J. Cha, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129-4404. Email: cha{at}helix.mgh.harvard.edu

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				N. A. Aziz, C. K. Jurgens, G. B. Landwehrmeyer, EHDN Registry Study Group, W.M.C. van Roon-Mom, G. J.B. van Ommen, T. Stijnen, and R. A.C. Roos Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease Neurology, October 20, 2009; 73(16): 1280 - 1285. [Abstract] [Full Text] [PDF]

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