Synthetic transcription elongation factors license transcription across repressive chromatin

The release of paused RNA polymerase IIinto productive elongationis 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 elongationmachinery. 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 frataxinexpression in Friedreich’s ataxia, a terminal neurodegenerative disease with no effective therapy. The modular designof Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongationat targeted genomic loci.