Sivasankaran, Rajeev, Teider, Natalia, Mcnally, Anna, Bradner, Jay and Worringer, Katie (2017) Synthetic Transcription Elongation Factors license transcription across repressive heterochromatin. Science. pp. 1617-1622.

Abstract

Switching a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes involved in human development and disease. To exert control on 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 binds a component of the transcription elongation machinery. The resultant bifunctional molecules convert constituent modules from broad-spectrum inhibitors of transcription into a gene-specific stimulator of transcriptional elongation. Here, we present Syn-TEF1, a molecule that actively facilitates transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a debilitating and ultimately lethal neurodegenerative disease with no effective therapy. Our modular design provides a framework for generating a class of molecules that license transcription elongation at targeted genomic loci.

Item Type:	Article
Date Deposited:	16 Jan 2018 00:45
Last Modified:	16 Jan 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33853