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J Neurochem. 2011 Feb;116(3):415-25. doi: 10.1111/j.1471-4159.2010.07122.x. Epub 2010 Dec 13.

Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease.

Author information

  • 1Department of Neuroscience and Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, The James Black Centre, London, UK.

Abstract

Transcriptional dysfunction is a prominent hallmark of Huntington's disease (HD). Several transcription factors have been implicated in the aetiology of HD progression and one of the most prominent is repressor element 1 (RE1) silencing transcription factor (REST). REST is a global repressor of neuronal gene expression and in the presence of mutant Huntingtin increased nuclear REST levels lead to elevated RE1 occupancy and a concomitant increase in target gene repression, including brain-derived neurotrophic factor. It is of great interest to devise strategies to reverse transcriptional dysregulation caused by increased nuclear REST and determine the consequences in HD. Thus far, such strategies have involved RNAi or mutant REST constructs. Decoys are double-stranded oligodeoxynucleotides corresponding to the DNA-binding element of a transcription factor and act to sequester it, thereby abrogating its transcriptional activity. Here, we report the use of a novel decoy strategy to rescue REST target gene expression in a cellular model of HD. We show that delivery of the decoy in cells expressing mutant Huntingtin leads to its specific interaction with REST, a reduction in REST occupancy of RE1s and rescue of target gene expression, including Bdnf. These data point to an alternative strategy for rebalancing the transcriptional dysregulation in HD.

© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

PMID:
21105876
[PubMed - indexed for MEDLINE]
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