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- Title
The artificial 4-zinc-finger protein Bagly binds human utrophin promoter A at the endogenous chromosomal site and activates transcription.
- Authors
Onori, Annalisa; Desantis, Agata; Buontempo, Serena; Di Certo, Maria Grazia; Fanciulli, Maurizio; Salvatori, Luisa; Passananti, Claudio; Corbi, Nicoletta
- Abstract
Our aim is to upregulate the expression of the dystrophin-related gene utrophin in Duchenne muscular dystrophy, in this way complementing the lack of dystrophin function. To achieve utrophin upregulation, we designed and engineered synthetic zinc-finger based transcription factors. We have previously shown that the artificial 3-zinc-finger protein Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from utrophin promoter A. Here we report a novel artificial 4-zinc-finger protein, Bagly, which binds with optimized affinity–specificity to a 12 bp DNA target sequence that is internal to human utrophin promoter A. Bagly was generated adding to Jazz protein an extra-fourth zinc finger, derived from transcription factor YY1. Importantly, the Bagly DNA target sequence is statistically present in the human genome only 210 times, about 60 fewer times than the 9 bp Jazz DNA target sequence. Thanks to its additional zinc-finger domain, Bagly protein shows enhanced transcriptional activity. Moreover, we demonstrated Bagly’s effective access and binding to active chromatin in the chromosomal context and its ability to upregulate endogenous utrophin.
- Subjects
DYSTROPHIN; CYTOSKELETAL proteins; GENES; TRANSCRIPTION factors; DNA
- Publication
Biochemistry & Cell Biology, 2007, Vol 85, Issue 3, p358
- ISSN
0829-8211
- Publication type
Article
- DOI
10.1139/O07-015