title: Identification of REST-regulated genes and pathways using a REST-targeted antisense approach.
abstract: The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is one of the first negative-acting transcriptional regulators implicated in vertebrate development thought to regulate hundreds of neuron-specific genes. However, its function in the adult system remains elusive. Here we employ second-generation antisense oligonucleotides (ASOs) to study the impact of rest-mediated suppression on gene expression. We demonstrate specific reductions in REST levels in vitro, and in vivo in mouse liver following treatment with ASOs, and we show that ASO mediated-REST suppression results in the elevation in expression of many neuronal genes including brain-derived neurotrophic factor, Synapsin1 (syn1) and β3-tubulin in BALB/c liver. Furthermore, we show the elevation of the affected proteins in plasma following ASO treatment. Finally, microarray analysis was applied to identify a broad range of genes modulated by REST suppression in mouse liver. Our findings suggest that REST may be an important target for neurodegenerative diseases like Huntington's disease, is also involved in the regulation of a broad range of additional cellular pathways, and that the antisense approach is a viable strategy for selectively modulating REST activity in vivo.
authors: 1 Department of Molecular Neurobiology, Evotec AG , Hamburg, Germany .
authors: Yalda
authors: Y
authors: Sedaghat
authors: Huynh-Hoa
authors: HH
authors: Bui
authors: Curt
authors: C
authors: Mazur
authors: Brett P
authors: BP
authors: Monia
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D000099229:RE1-Silencing Transcription Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016376:Oligonucleotides, Antisense; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor