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
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Science. 2017 Dec 22;358(6370):1617-1622. doi: 10.1126/science.aan6414. Epub 2017 Nov 30.
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.
暂停的RNA聚合酶II进入有效延伸的过程受到高度调控，尤其是在影响人类发育和疾病的基因处。为了控制这一限速步骤，我们设计了序列特异性的合成转录延伸因子（Syn-TEFs）。这些分子由可编程的DNA结合配体组成，这些配体与一个小分子灵活连接，该小分子与转录延伸机制相互作用。通过将活性限制在靶向位点，Syn-TEFs将组成模块从广谱转录抑制剂转变为基因特异性刺激剂。在这里，我们展示了Syn-TEF1，一种能够在导致弗里德赖希共济失调（一种无有效治疗方法的终末期神经退行性疾病）中使frataxin表达沉默的抑制性GAA重复序列上积极促进转录的分子。Syn-TEF1的模块化设计为开发一类能够在靶向基因组位点许可转录延伸的分子定义了一个通用框架。
