Synthetic transcription elongation factors license transcription across repressive chromatin

Science. 2017 Dec 22;358(6370):1617-1622. doi: 10.1126/science.aan6414. Epub 2017 Nov 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / metabolism*
  • Friedreich Ataxia / genetics*
  • Gene Silencing
  • Humans
  • Iron-Binding Proteins / genetics*
  • RNA Polymerase II / metabolism
  • Transcription, Genetic
  • Transcriptional Activation*
  • Transcriptional Elongation Factors / chemical synthesis*
  • Transcriptional Elongation Factors / metabolism*

Substances

  • Chromatin
  • Iron-Binding Proteins
  • Transcriptional Elongation Factors
  • frataxin
  • RNA Polymerase II