title: Utrophin up-regulation by an artificial transcription factor in transgenic mice.
abstract: Duchenne Muscular Dystrophy (DMD) is a severe muscle degenerative disease, due to absence of dystrophin. There is currently no effective treatment for DMD. Our aim is to up-regulate the expression level of the dystrophin related gene utrophin in DMD, complementing in this way the lack of dystrophin functions. To this end we designed and engineered several synthetic zinc finger based transcription factors. In particular, we have previously shown that the artificial three zinc finger protein named Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from the utrophin promoter "A". Here we report on the characterization of Vp16-Jazz-transgenic mice that specifically over-express the utrophin gene at the muscular level. A Chromatin Immunoprecipitation assay (ChIP) demonstrated the effective access/binding of the Jazz protein to active chromatin in mouse muscle and Vp16-Jazz was shown to be able to up-regulate endogenous utrophin gene expression by immunohistochemistry, western blot analyses and real-time PCR. To our knowledge, this is the first example of a transgenic mouse expressing an artificial gene coding for a zinc finger based transcription factor. The achievement of Vp16-Jazz transgenic mice validates the strategy of transcriptional targeting of endogenous genes and could represent an exclusive animal model for use in drug discovery and therapeutics.
authors: Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, European Brain Research Institute, Rome, Italy.
authors: Elisabetta
authors: E
authors: Mattei
authors: Nicoletta
authors: N
authors: Corbi
authors: Maria Grazia
authors: MG
authors: Di Certo
authors: Georgios
authors: G
authors: Strimpakos
authors: Cinzia
authors: C
authors: Severini
authors: Annalisa
authors: A
authors: Onori
authors: Agata
authors: A
authors: Desantis
authors: Valentina
authors: V
authors: Libri
authors: Serena
authors: S
authors: Buontempo
authors: Aristide
authors: A
authors: Floridi
authors: Maurizio
authors: M
authors: Fanciulli
authors: Dilair
authors: D
authors: Baban
authors: Kay E
authors: KE
authors: Davies
authors: Claudio
authors: C
authors: Passananti
mesh_terms: D000818:Animals; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D049411:Utrophin / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D049411:Utrophin
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