Selective gene regulation with designed transcription factors: implications for therapy.
The prospect of selectively regulating gene expression is highly appealing, both for laboratory investigations and for potential therapeutic applications. This possibility has recently become a reality through the use of designed transcription factors (DTFs). This approach makes use of the DNA-binding domains of native transcription factors as scaffolds, but then introduces new DNA recognition capabilities that allow selective recognition of the regulatory regions of individual genes. The DTF strategy allows either upregulation or downregulation of transcription. This differs from approaches such as antisense or RNA interference that are intended only to inhibit gene expression. Much of the work to date on DTFs has exploited the modular nature of Cys2-His2 zinc finger (Zif) modules that, when coupled with the use of phage display or other combinatorial library techniques, allow the creation of novel and selective DNA recognition domains. These domains can then be linked to transcriptional regulatory moieties, including transactivator or repressor domains, to modulate gene expression. Recent progress has demonstrated that DTFs can selectively regulate the transcription of endogenous genes in mammalian cells and in living animals.
Falke
Dietmar
D
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
Juliano
Rudy L
RL
D000256:Adenoviridae; D000818:Animals; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D015202:Protein Engineering; D012190:Retroviridae; D014157:Transcription Factors / Q000378:metabolism / Q000627:therapeutic use*; D014162:Transfection; D016335:Zinc Fingers / Q000502:physiology
D014157:Transcription Factors; D004247:DNA