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The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Buckley, N. J., Johnson, R., Zuccato, C., Bithell, A. and Cattaneo, E. (2010) The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease. Neurobiology of Disease, 39 (1). pp. 28-39. ISSN 1095-953x

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To link to this item DOI: 10.1016/j.nbd.2010.02.003


Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Item Type:Article
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
ID Code:34709
Uncontrolled Keywords:Huntington's disease; Hungtingtin; Transcription; Post-transcriptional; RE1 silencing transcription factor (REST); Brain-derived-neurotrophic-factor (BDNF); MicroRNAs; Long non-coding BNAs; Histone; Histone deacetylase; Histone acetylation; Histone methylation; Chromatin; Chromatin immunoprecipitation; Epigenetic; Microarray; Biomarker; Synthetic peptide nucleic acid; Dominant-negative REST, RNAi

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