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Polyglutamine Expanded Huntingtin Dramatically Alters the Genome-Wide Binding of HSF1

Article type: Research Article

Authors: Riva, Laura | Koeva, Martina; | Yildirim, Ferah | Pirhaji, Leila | Dinesh, Deepika | Mazor, Tali | Duennwald, Martin L. | Fraenkel, Ernest

Affiliations: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA | The Whitehead Institute for Biomedical Research, Cambridge, MA, USA | Boston Biomedical Research Institute, Watertown, MA, USA

Note: [] The first two authors contributed equally to this work. Present Address: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, at the IFOM-IEO campus, Milan, Italy

Note: [] The first two authors contributed equally to this work.

Note: [] Correspondence to: Ernest Fraenkel, Department of Biological Engineering, Bldg. 16-241, Massachusetts Institute of Technology, 77 Mass. Ave., Cambridge, MA 02139, USA. Tel.: +1 617 452 4086; Fax: +1 617 258 8676; E-mail: [email protected]

Keywords: Huntington disease, heat shock transcription factor, heat-shock response, chromatin immunoprecipitation, cDNA microarrays, deep sequencing

DOI: 10.3233/JHD-2012-120020

Journal: Journal of Huntington's Disease, vol. 1, no. 1, pp. 33-45, 2012

Published: 2012
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Abstract

In Huntington's disease (HD), polyglutamine expansions in the huntingtin (Htt) protein cause subtle changes in cellular functions that, over-time, lead to neurodegeneration and death. Studies have indicated that activation of the heat shock response can reduce many of the effects of mutant Htt in disease models, suggesting that the heat shock response is impaired in the disease. To understand the basis for this impairment, we have used genome-wide chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) to examine the effects of mutant Htt on the master regulator of the heat shock response, HSF1. We find that, under normal conditions, HSF1 function is highly similar in cells carrying either wild-type or mutant Htt. However, polyQ-expanded Htt severely blunts the HSF1-mediated stress response. Surprisingly, we find that the HSF1 targets most affected upon stress are not directly associated with proteostasis, but with cytoskeletal binding, focal adhesion and GTPase activity. Our data raise the intriguing hypothesis that the accumulated damage from life-long impairment in these stress responses may contribute significantly to the etiology of Huntington's disease.

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