Nucleic Acids Research, 1993, Vol. 21, No. 12 2789-2796
© 1993
MOLECULAR BIOLOGY |
In vivo transcription of a progesterone-responsive gene is specifically inhibited by a triplex-forming oligonucleotide
Department of Cell Biology, Baylor College of Medicine Houston, TX 77030 1Center for Biotechnology, Baylor College of Medicine Woodlands, TX 77381 2Triplex Pharmaceutical Corporation 9391A Grogins Mill Road, Woodlands, TX 77380, USA
*To whom correspondence should be addressed
Received May 12, 1993. Accepted May 18, 1993.
Oligonucleotides provide novel reagents for Inhibition of gene expression because of their high affinity binding to specific nucleotide sequences. We describe a 38 base, single-stranded DNA that forms a triple helix or ‘triplex’ on progesterone response elements of a target gene. This triplex-forming oligonucleotide binds with a Kd= 100 nM at 37°C and physiological pH, and blocks binding of progesterone receptors to the target. Furthermore, It completely inhibited progesterone receptor-dependent transcription In vitro. To approach In vivo conditions, triplex-forming ollgonucleotides were tested In cell transfection studies. The derivation of the oligonucleotides with cholesterol enhanced their cellular uptake and nuclear concentration by at least four-fold. The cholesterol-derivatized triplex-forming oligonucleotide specifically inhibited transcription of the PRE-containing reporter gene in cells when applied to the medium at micromolar concentrations. This Is the first demonstration of steroid-responsive gene inhibition by triplex formation and joins the growing body of evidence Indicating that oligonucleotides have therapeutic potential.
+Present address: Department of Animal Science, Texas A & M University, College Station, TX 77843, USA
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