title: Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease.
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.
authors.affiliation: Department of Neuroscience and Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, The James Black Centre, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Soldati
authors.forename: Angela
authors.initials: A
authors.lastname: Bithell
authors.forename: Paola
authors.initials: P
authors.lastname: Conforti
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055879:Gene Knock-In Techniques; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics* / Q000494:pharmacology* / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C086055:HTT protein, human