Utrophin Up-Regulation by an Artificial Transcription Factor in Transgenic Mice

Hdl Handle:
http://hdl.handle.net/10675.2/536
Title:
Utrophin Up-Regulation by an Artificial Transcription Factor in Transgenic Mice
Authors:
Mattei, Elisabetta; Corbi, Nicoletta; Di Certo, Maria Grazia; Strimpakos, Georgios; Severini, Cinzia; Onori, Annalisa; Desantis, Agata; Libri, Valentina; Buontempo, Serena; Floridi, Aristide; Fanciulli, Maurizio; Baban, Dilair; Davies, Kay E. ( 0000-0001-8807-8520 ) ; Passananti, Claudio
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 â Aâ . 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.
Editors:
Mei, Lin
Citation:
PLoS ONE. 2007 Aug 22; 2(8):e774
Issue Date:
22-Aug-2007
URI:
http://hdl.handle.net/10675.2/536
DOI:
10.1371/journal.pone.0000774
PubMed ID:
17712422
PubMed Central ID:
PMC1942121
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorMattei, Elisabettaen_US
dc.contributor.authorCorbi, Nicolettaen_US
dc.contributor.authorDi Certo, Maria Graziaen_US
dc.contributor.authorStrimpakos, Georgiosen_US
dc.contributor.authorSeverini, Cinziaen_US
dc.contributor.authorOnori, Annalisaen_US
dc.contributor.authorDesantis, Agataen_US
dc.contributor.authorLibri, Valentinaen_US
dc.contributor.authorBuontempo, Serenaen_US
dc.contributor.authorFloridi, Aristideen_US
dc.contributor.authorFanciulli, Maurizioen_US
dc.contributor.authorBaban, Dilairen_US
dc.contributor.authorDavies, Kay E.en_US
dc.contributor.authorPassananti, Claudioen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:33Z-
dc.date.available2012-10-26T16:26:33Z-
dc.date.issued2007-08-22en_US
dc.identifier.citationPLoS ONE. 2007 Aug 22; 2(8):e774en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid17712422en_US
dc.identifier.doi10.1371/journal.pone.0000774en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/536-
dc.description.abstractDuchenne 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 â Aâ . 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.en_US
dc.rightsMattei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiotechnologyen_US
dc.subjectMolecular Biologyen_US
dc.subjectNeurological Disorders/Neuromuscular Diseasesen_US
dc.titleUtrophin Up-Regulation by an Artificial Transcription Factor in Transgenic Miceen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC1942121en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

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