Activation of gene expression by small molecule transcription factors

Eukaryotic transcriptional activators are minimally comprised of a DNA bind ing domain and a separable activation domain; most activator proteins also bear a dimerization module. We have replaced these protein modules with syn thetic counterparts to create artificial transcription factors. One of thes e, at 4.2 kDa, mediates high levels of DNA site-specific transcriptional ac tivation in vitro. This molecule contains a sequence-specific DNA binding p olyamide in place of the typical DNA binding region and a nonprotein linker in place of the usual dimerization peptide. Thus our activating region, a designed peptide, functions outside of the archetypal protein context, as l ong as it is tethered to DNA, Because synthetic polyamides can, in principl e, be designed to recognize any specific sequence, these results represent a key step toward the design of small molecules that can up-regulate any sp ecified gene.