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Synthetic Transcription Elongation Factors license transcription across repressive heterochromatin

Sivasankaran, Rajeev and Teider, Natalia and Mcnally, Anna and 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

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