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Utrophin up-regulation by an artificial transcription factor in transgenic mice.
- Source :
-
PloS one [PLoS One] 2007 Aug 22; Vol. 2 (8), pp. e774. Date of Electronic Publication: 2007 Aug 22. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Herpes Simplex Virus Protein Vmw65 genetics
Herpes Simplex Virus Protein Vmw65 metabolism
Humans
Mice
Microarray Analysis
Muscle Contraction physiology
Muscle, Skeletal cytology
Muscle, Skeletal metabolism
Muscular Dystrophy, Duchenne genetics
Muscular Dystrophy, Duchenne metabolism
Recombinant Fusion Proteins genetics
Tissue Distribution
Transcription Factors genetics
Utrophin genetics
Zinc Fingers genetics
Mice, Transgenic
Recombinant Fusion Proteins metabolism
Transcription Factors metabolism
Up-Regulation
Utrophin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 2
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 17712422
- Full Text :
- https://doi.org/10.1371/journal.pone.0000774