Systematic mapping of functional enhancer-promoter connections with CRISPR interference

被引：402

作者：

Fulco, Charles P. ^{[1
,2
]}

Munschauer, Mathias ^{[1
]}

Anyoha, Rockwell ^{[1
]}

Munson, Glen ^{[1
]}

Grossman, Sharon R. ^{[1
,3
,4
]}

Perez, Elizabeth M. ^{[1
]}

Kane, Michael ^{[1
]}

Cleary, Brian ^{[1
,5
]}

Lander, Eric S. ^{[1
,2
,4
]}

Engreitz, Jesse M. ^{[1
]}

机构：

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

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

[3] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA

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

[5] MIT, Computat & Syst Biol Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

SCIENCE | 2016年 / 354卷 / 6313期

关键词：

HUMAN GENOME; TRANSCRIPTION; ELEMENTS; GENE; DIFFERENTIATION; REVEALS; BINDING; CELLS; DNA;

D O I：

10.1126/science.aag2445

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：

Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess >1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.

引用

页码：769 / 773

页数：5

共 24 条

[1] Functional and Mechanistic Diversity of Distal Transcription Enhancers [J].

Bulger, Michael ;

Groudine, Mark .

CELL, 2011, 144 (03) :327-339

[2]

Burdett T., The NHGRI-EBI Catalog of published genome-wide association studies

[3] BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis [J].

Canver, Matthew C. ;

Smith, Elenoe C. ;

Sher, Falak ;

Pinello, Luca ;

Sanjana, Neville E. ;

Shalem, Ophir ;

Chen, Diane D. ;

Schupp, Patrick G. ;

Vinjamur, Divya S. ;

Garcia, Sara P. ;

Luc, Sidinh ;

Kurita, Ryo ;

Nakamura, Yukio ;

Fujiwara, Yuko ;

Maeda, Takahiro ;

Yuan, Guo-Cheng ;

Zhang, Feng ;

Orkin, Stuart H. ;

Bauer, Daniel E. .

NATURE, 2015, 527 (7577) :192-+

[4] DEVELOPMENTAL REGULATION OF BETA-GLOBIN GENE SWITCHING [J].

CHOI, ORB ;

ENGEL, JD .

CELL, 1988, 55 (01) :17-26

[5] An integrated encyclopedia of DNA elements in the human genome [J].

Dunham, Ian ;

Kundaje, Anshul ;

Aldred, Shelley F. ;

Collins, Patrick J. ;

Davis, CarrieA. ;

Doyle, Francis ;

Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

[6] Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders (vol 13, pg 673, 2014) [J].

Falkenberg, Katrina J. ;

Johnstone, Ricky W. .

NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (03) :219-219

[7]

Fujieda A, 2005, INT J ONCOL, V27, P743

[8] Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation [J].

Gilbert, Luke A. ;

Horlbeck, Max A. ;

Adamson, Britt ;

Villalta, Jacqueline E. ;

Chen, Yuwen ;

Whitehead, Evan H. ;

Guimaraes, Carla ;

Panning, Barbara ;

Ploegh, Hidde L. ;

Bassik, Michael C. ;

Qi, Lei S. ;

Kampmann, Martin ;

Weissman, Jonathan S. .

CELL, 2014, 159 (03) :647-661

[9] CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes [J].

Gilbert, Luke A. ;

Larson, Matthew H. ;

Morsut, Leonardo ;

Liu, Zairan ;

Brar, Gloria A. ;

Torres, Sandra E. ;

Stern-Ginossar, Noam ;

Brandman, Onn ;

Whitehead, Evan H. ;

Doudna, Jennifer A. ;

Lim, Wendell A. ;

Weissman, Jonathan S. ;

Qi, Lei S. .

CELL, 2013, 154 (02) :442-451

[10] Targeted Deletion of Multiple CTCF-Binding Elements in the Human C-MYC Gene Reveals a Requirement for CTCF in C-MYC Expression [J].

Gombert, Wendy M. ;

Krumm, Anton .

PLOS ONE, 2009, 4 (07)

← 1 2 3 →