Polyglutamine Expanded Huntingtin Dramatically Alters the Genome-Wide Binding of HSF1
| Autor: | Ernest Fraenkel, Leila Pirhaji, Tali Mazor, Martina Koeva, Ferah Yildirim, Deepika Dinesh, Laura Riva, Martin L. Duennwald |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Whitehead Institute for Biomedical Research, Riva, Laura, Koeva, Martina I., Yildirim, Ferah, Pirhaji, Leila, Dinesh, Deepika, Mazor, Tali, Fraenkel, Ernest |
| Rok vydání: | 2012 |
| Předmět: |
Genetics
congenital hereditary and neonatal diseases and abnormalities Huntingtin fungi Neurodegeneration Biology medicine.disease Cell biology Heat shock factor Cellular and Molecular Neuroscience Proteostasis Huntington's disease mental disorders medicine Huntingtin Protein Neurology (clinical) Heat shock HSF1 |
| Zdroj: | PMC |
| ISSN: | 1879-6397 |
| Popis: | 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. National Institutes of Health (U.S.) (Grant R24 DK-090963) National Institutes of Health (U.S.) (Grant R01-GM089903) National Institutes of Health (U.S.) (Grant P30-ES002109) National Science Foundation (U.S.) (Award DB1-0821391) |
| Databáze: | OpenAIRE |
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