title: Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease.
abstract: Huntingtin is a protein that is mutated in Huntington's disease (HD), a dominant inherited neurodegenerative disorder. We previously proposed that, in addition to the gained toxic activity of the mutant protein, selective molecular dysfunctions in HD may represent the consequences of the loss of wild-type protein activity. We first reported that wild-type huntingtin positively affects the transcription of the brain-derived neurotrophic factor (BDNF) gene, a cortically derived survival factor for the striatal neurons that are mainly affected in the disease. Mutation in huntingtin decreases BDNF gene transcription. One mechanism involves the activation of repressor element 1/neuron-restrictive silencer element (RE1/NRSE) located within the BDNF promoter. We now show that increased binding of the RE1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) repressor occurs at multiple genomic RE1/NRSE loci in HD cells, in animal models, and in postmortem brains, resulting in a decrease of RE1/NRSE-mediated gene transcription. The same molecular phenotype is produced in cells and brain tissue depleted of endogenous huntingtin, thereby directly validating the loss-of-function hypothesis of HD. Through a ChIP (chromatin immunoprecipitation)-on-chip approach, we examined occupancy of multiple REST/NRSF target genes in the postmortem HD brain, providing the first example of the application of this technology to neurodegenerative diseases. Finally, we show that attenuation of REST/NRSF binding restores BDNF levels, suggesting that relief of REST/NRSF mediated repression can restore aberrant neuronal gene transcription in HD.
authors.affiliation: Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milan, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zuccato
authors.forename: Nikolai
authors.initials: N
authors.lastname: Belyaev
authors.forename: Paola
authors.initials: P
authors.lastname: Conforti
authors.forename: Lezanne
authors.initials: L
authors.lastname: Ooi
authors.forename: Marzia
authors.initials: M
authors.lastname: Tartari
authors.forename: Evangelia
authors.initials: E
authors.lastname: Papadimou
authors.forename: Marcy
authors.initials: M
authors.lastname: MacDonald
authors.forename: Elisa
authors.initials: E
authors.lastname: Fossale
authors.forename: Scott
authors.initials: S
authors.lastname: Zeitlin
authors.forename: Noel
authors.initials: N
authors.lastname: Buckley
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C506812:Htt protein, mouse