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Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington’s disease
- Source :
- Journal of Neurochemistry. 116:415-425
- Publication Year :
- 2010
- Publisher :
- Wiley, 2010.
-
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.
- Subjects :
- Genetics
0303 health sciences
Huntingtin
Repressor
Biology
Biochemistry
Cell biology
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
RNA interference
Gene expression
Huntingtin Protein
Gene silencing
Decoy
Transcription factor
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- ISSN :
- 00223042
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Journal of Neurochemistry
- Accession number :
- edsair.doi...........fe9d7326bfca4ef6421e507e9dbe6300