CTF/NF1 transcription factors act as potent genetic insulators for integrating gene transfer vectors.

Details

Serval ID
serval:BIB_CB32741F814E
Type
Article: article from journal or magazin.
Collection
Publications
Title
CTF/NF1 transcription factors act as potent genetic insulators for integrating gene transfer vectors.
Journal
Gene Therapy
Author(s)
Gaussin A., Modlich U., Bauche C., Niederländer N.J., Schambach A., Duros C., Artus A., Baum C., Cohen-Haguenauer O., Mermod N.
ISSN
1476-5462 (Electronic)
ISSN-L
0969-7128
Publication state
Published
Issued date
2012
Volume
19
Number
1
Pages
15-24
Language
english
Abstract
Gene transfer-based therapeutic approaches have greatly benefited from the ability of some viral vectors to efficiently integrate within the cell genome and ensure persistent transmission of newly acquired transgenes to the target cell progeny. However, integration of provirus has been associated with epigenetic repercussions that may influence the expression of both the transgene and cellular genes close to vector integration loci. The exploitation of genetic insulator elements may overcome both issues through their ability to act as barriers that limit transgene silencing and/or as enhancer-blockers preventing the activation of endogenous genes by the vector enhancer. We established quantitative plasmid-based assay systems to screen enhancer-blocker and barrier genetic elements. Short synthetic insulators that bind to nuclear factor-I protein family transcription factors were identified to exert both enhancer-blocker and barrier functions, and were compared to binding sites for the insulator protein CTCF (CCCTC-binding factor). Gamma-retroviral vectors enclosing these insulator elements were produced at titers similar to their non-insulated counterparts and proved to be less genotoxic in an in vitro immortalization assay, yielding lower activation of Evi1 oncogene expression and reduced clonal expansion of bone marrow cells.
Keywords
oncogene, insulators, CTF/NF1, CTCF, genome integration, genotoxicity
Pubmed
Web of science
Open Access
Yes
Create date
24/02/2011 12:27
Last modification date
20/08/2019 16:46
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