title: Poly-glutamine expanded huntingtin dramatically alters the genome wide binding of HSF1.
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.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, 77 Mass Ave., Cambridge, MA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Riva
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.forename: Leila
authors.initials: L
authors.lastname: Pirhaji
authors.forename: Deepika
authors.initials: D
authors.lastname: Dinesh
authors.forename: Tali
authors.initials: T
authors.lastname: Mazor
authors.forename: Martin L
authors.initials: ML
authors.lastname: Duennwald
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D023281:Genomics; D000076249:Heat Shock Transcription Factors; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; C086055:HTT protein, human; D000076249:Heat Shock Transcription Factors; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D014157:Transcription Factors; C097188:polyglutamine