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The Journal of Neuroscience, June 27, 2007, 27(26):6972-6983; doi:10.1523/JNEUROSCI.4278-06.2007

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Neurobiology of Disease
Widespread Disruption of Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor Occupancy at Its Target Genes in Huntington's Disease

Chiara Zuccato,^1 * Nikolai Belyaev,^2 * Paola Conforti,¹ Lezanne Ooi,² Marzia Tartari,¹ Evangelia Papadimou,¹ Marcy MacDonald,³ Elisa Fossale,³ Scott Zeitlin,⁴ Noel Buckley,⁵  and Elena Cattaneo¹ 

¹Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milan, Via Balzaretti 9, 20133 Milano, Italy, ²Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom, ³Center for Human Genetic Research, Massachusetts General Hospital Richard B. Simches Research Center, Boston, Massachusetts 02114, ⁴Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, and ⁵Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom

Correspondence should be addressed to either of the following: Prof. Elena Cattaneo, Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milano, Via Balzaretti 9, 20133 Milano, Italy, Email: elena.cattaneo{at}unimi.it; or Prof. Noel Buckley, Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London,125 Coldharbour Lane, London SE5 9NU, UK, Email: noel.buckley{at}iop.kcl.ac.uk

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.

Key words: BDNF; genome; Huntington's disease; neuronal death; REST/NRSF; transcription

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Received June 23, 2006; revised April 30, 2007; accepted May 1, 2007.

Correspondence should be addressed to either of the following: Prof. Elena Cattaneo, Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milano, Via Balzaretti 9, 20133 Milano, Italy, Email: elena.cattaneo{at}unimi.it; or Prof. Noel Buckley, Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London,125 Coldharbour Lane, London SE5 9NU, UK, Email: noel.buckley{at}iop.kcl.ac.uk

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