Synthetic transcription elongation factors license transcription across repressive chromatin

被引：106

作者：

Erwin, Graham S. ^{[1
]}

Grieshop, Matthew P. ^{[1
]}

Ali, Asfa ^{[1
]}

Qi, Jun ^{[2
]}

Lawlor, Matthew ^{[2
]}

Kumar, Deepak ^{[3
,4
]}

Ahmad, Istaq ^{[3
,4
]}

McNally, Anna ^{[5
]}

Teider, Natalia ^{[5
]}

Worringer, Katie ^{[5
]}

Sivasankaran, Rajeev ^{[5
]}

Syed, Deeba N. ^{[6
]}

Eguchi, Asuka ^{[1
]}

Ashraf, Md. ^{[1
]}

Jeffery, Justin ^{[7
]}

Xu, Mousheng ^{[2
]}

Park, Paul M. C. ^{[2
]}

Mukhtar, Hasan ^{[6
]}

Srivastava, Achal K. ^{[3
]}

Faruq, Mohammed ^{[4
]}

Bradner, James E. ^{[2
,5
]}

Ansari, Aseem Z. ^{[1
,8
]}

机构：

[1] Univ Wisconsin Madison, Dept Biochem, Madison, WI 53706 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[3] All India Inst Med Sci, Dept Neurol, New Delhi, India

[4] CSIR, IGIB, Genom & Mol Med, New Delhi, India

[5] NIBR, Cambridge, MA 02139 USA

[6] Univ Wisconsin Madison, Dept Dermatol, Madison, WI 53706 USA

[7] Univ Wisconsin, Carbone Canc Ctr, Small Anim Imaging Facil, Madison, WI 53792 USA

[8] Univ Wisconsin Madison, Genome Ctr Wisconsin, Madison, WI 53706 USA

来源：

SCIENCE | 2017年 / 358卷 / 6370期

关键词：

FRIEDREICH ATAXIA; CELL FATE; GENE; DNA; REPEATS; INHIBITION; MOLECULES; COMPLEX;

D O I：

10.1126/science.aan6414

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1617 / 1621

页数：5

共 30 条

[1] Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans [J].

Adelman, Karen ;

Lis, John T. .

NATURE REVIEWS GENETICS, 2012, 13 (10) :720-731

[2] DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA•TTC repeats in Friedreich's ataxia [J].

Burnett, Ryan ;

Melander, Christian ;

Puckett, James W. ;

Son, Leslie S. ;

Wells, Robert D. ;

Dervan, Peter B. ;

Gottesfeld, Joel M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (31) :11497-11502

[3] Specificity landscapes of DNA binding molecules elucidate biological function [J].

Carlson, Clayton D. ;

Warren, Christopher L. ;

Hauschild, Karl E. ;

Ozers, Mary S. ;

Qadir, Naveeda ;

Bhimsaria, Devesh ;

Lee, Youngsook ;

Cerrina, Franco ;

Ansari, Aseem Z. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (10) :4544-4549

[4] A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins [J].

Chapdelaine, Pierre ;

Coulombe, Zoe ;

Chikh, Amina ;

Gerard, Catherine ;

Tremblay, Jacques P. .

MOLECULAR THERAPY-NUCLEIC ACIDS, 2013, 2 :e119

[5] A gene expression phenotype in lymphocytes from friedreich ataxia patients [J].

Coppola, Giovanni ;

Burnett, Ryan ;

Perlman, Susan ;

Versano, Revital ;

Gao, Fuying ;

Plasterer, Heather ;

Rai, Myriam ;

Sacca, Francesco ;

Filla, Alessandro ;

Lynch, David R. ;

Rusche, James R. ;

Gottesfeld, Joel M. ;

Pandolfo, Massimo ;

Geschwind, Daniel H. .

ANNALS OF NEUROLOGY, 2011, 70 (05) :790-804

[6] Molecular recognition of DNA by small molecules [J].

Dervan, PB .

BIOORGANIC & MEDICINAL CHEMISTRY, 2001, 9 (09) :2215-2235

[7] Reprogramming cell fate with a genome-scale library of artificial transcription factors [J].

Eguchi, Asuka ;

Wleklinski, Matthew J. ;

Spurgat, Mackenzie C. ;

Heiderscheit, Evan A. ;

Kropornicka, Anna S. ;

Vu, Catherine K. ;

Bhimsaria, Devesh ;

Swanson, Scott A. ;

Stewart, Ron ;

Ramanathan, Parameswaran ;

Kamp, Timothy J. ;

Slukvin, Igor ;

Thomson, James A. ;

Dutton, James R. ;

Ansari, Aseem Z. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (51) :E8257-E8266

[8] Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers [J].

Eguchi, Asuka ;

Lee, Garrett O. ;

Wan, Fang ;

Erwin, Graham S. ;

Ansari, Aseem Z. .

BIOCHEMICAL JOURNAL, 2014, 462 :397-413

[9] Synthetic genome readers target clustered binding sites across diverse chromatin states [J].

Erwin, Graham S. ;

Grieshop, Matthew P. ;

Bhimsaria, Devesh ;

Do, Truman J. ;

Rodriguez-Martinez, Jose A. ;

Mehta, Charu ;

Khanna, Kanika ;

Swanson, Scott A. ;

Stewart, Ron ;

Thomson, James A. ;

Ramanathan, Parameswaran ;

Ansari, Aseem Z. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (47) :E7418-E7427

[10] Selective inhibition of BET bromodomains [J].

Filippakopoulos, Panagis ;

Qi, Jun ;

Picaud, Sarah ;

Shen, Yao ;

Smith, William B. ;

Fedorov, Oleg ;

Morse, Elizabeth M. ;

Keates, Tracey ;

Hickman, Tyler T. ;

Felletar, Ildiko ;

Philpott, Martin ;

Munro, Shonagh ;

McKeown, Michael R. ;

Wang, Yuchuan ;

Christie, Amanda L. ;

West, Nathan ;

Cameron, Michael J. ;

Schwartz, Brian ;

Heightman, Tom D. ;

La Thangue, Nicholas ;

French, Christopher A. ;

Wiest, Olaf ;

Kung, Andrew L. ;

Knapp, Stefan ;

Bradner, James E. .

NATURE, 2010, 468 (7327) :1067-1073

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