title: Specific micro RNA-regulated TetR-KRAB transcriptional control of transgene expression in viral vector-transduced cells.
abstract: Precise control of transgene expression in a tissue-specific and temporally regulated manner is desirable for many basic and applied investigations gene therapy applications. This is important to regulate dose of transgene products and minimize unwanted effects. Previously described methods have employed tissue specific promoters, miRNA-based transgene silencing or tetR-KRAB-mediated suppression of transgene promoters. To improve on versatility of transgene expression control, we have developed expression systems that use combinations of a tetR-KRAB artificial transgene-repressor, endogenous miRNA silencing machinery and tissue specific promoters. Precise control of transgene expression was demonstrated in liver-, macrophage- and muscle-derived cells. Efficiency was also demonstrated in vivo in murine muscle. This multicomponent and modular regulatory system provides a robust and easily adaptable method for achieving regulated transgene expression in different tissue types. The improved precision of regulation will be useful for many gene therapy applications requiring specific spatiotemporal transgene regulation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 948, Nantes, France. Virginie.pichard@univ-nantes.fr
authors.forename: Virginie
authors.initials: V
authors.lastname: Pichard
authors.forename: Dominique
authors.initials: D
authors.lastname: Aubert
authors.forename: Sebastien
authors.initials: S
authors.lastname: Boni
authors.forename: Severine
authors.initials: S
authors.lastname: Battaglia
authors.forename: Dejana
authors.initials: D
authors.lastname: Ivacik
authors.forename: Tuan Huy
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Patrick
authors.initials: P
authors.lastname: Arbuthnot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ferry
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D032342:Muscle Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D012097:Repressor Proteins; C034811:tetracycline resistance-encoding transposon repressor protein