An enhanced CRISPR repressor for targeted mammalian gene regulation

被引：296

作者：

Yeo, Nan Cher ^{[1
,2
]}

Chavez, Alejandro ^{[3
]}

Lance-Byrne, Alissa ^{[1
]}

Chan, Yingleong ^{[1
,2
]}

Menn, David ^{[4
]}

Milanova, Denitsa ^{[1
,2
]}

Kuo, Chih-Chung ^{[5
,6
]}

Guo, Xiaoge ^{[1
,2
]}

Sharma, Sumana ^{[7
]}

Tung, Angela ^{[1
]}

Cecchi, Ryan J. ^{[1
]}

Tuttle, Marcelle ^{[1
]}

Pradhan, Swechchha ^{[4
]}

Lim, Elaine T. ^{[1
,2
]}

Davidsohn, Noah ^{[1
,2
]}

Ebrahimkhani, Mo R. ^{[4
,8
]}

Collins, James J. ^{[1
,9
,10
,11
,12
]}

Lewis, Nathan E. ^{[5
,6
,13
]}

Kiani, Samira ^{[4
]}

Church, George M. ^{[1
,2
]}

机构：

[1] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA

[2] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[3] Columbia Univ Coll Phys & Surg, Dept Pathol & Cell Biol, 630 W 168th St, New York, NY 10032 USA

[4] Arizona State Univ, Ira A Fulton Sch Engn, Sch Biol & Hlth Syst Engn, Tempe, AZ 85287 USA

[5] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92103 USA

[6] Univ Calif San Diego, Novo Nordisk Fdn, Ctr Biosustainabil, San Diego, CA 92103 USA

[7] Wellcome Trust Sanger Inst, Cell Surface Signalling Lab, Cambridge, England

[8] Mayo Clin, Coll Med & Sci, Div Gastroenterol & Hematol, Phoenix, AZ USA

[9] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[10] MIT, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[11] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[13] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA

来源：

NATURE METHODS | 2018年 / 15卷 / 08期

关键词：

CPG-BINDING PROTEIN; TRANSCRIPTIONAL REPRESSION; HISTONE DEACETYLASE; DNA METHYLATION; HUMAN-CELLS; GENOME; CAS9; MECP2; EXPRESSION; ENDONUCLEASE;

D O I：

10.1038/s41592-018-0048-5

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.

引用

页码：611 / +

页数：11

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