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Erwin, Graham S.; Grieshop, Matthew P.; Ali, Asfa; Qi, Jun; Lawlor, Matthew; Kumar, Deepak; Ahmad, Istaq; McNally, Anna; Teider, Natalia; Worringer, Katie; Sivasankaran, Rajeev; Syed, Deeba N.; Eguchi, Asuka; Ashraf, Md; Jeffery, Justin; Xu, Mousheng; Park, Paul M. C.; Mukhtar, Hasan; Srivastava, Achal K.; Faruq, Mohammed; Bradner, James E.; Ansari, Aseem Z.
Science (American Association for the Advancement of Science), 12/2017, Volume: 358, Issue: 6370Journal Article
The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a terminal neurodegenerative disease with no effective therapy. The modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci.
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