Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations

被引：575

作者：

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

Nasser, Joseph ^{[1
]}

Jones, Thouis R. ^{[1
]}

Munson, Glen ^{[1
]}

Bergman, Drew T. ^{[1
]}

Subramanian, Vidya ^{[1
]}

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

Anyoha, Rockwell ^{[1
]}

Doughty, Benjamin R. ^{[1
]}

Patwardhan, Tejal A. ^{[1
]}

Nguyen, Tung H. ^{[1
]}

Kane, Michael ^{[1
]}

Perez, Elizabeth M. ^{[1
]}

Durand, Neva C. ^{[1
,4
,5
,7
]}

Lareau, Caleb A. ^{[1
]}

Stamenova, Elena K. ^{[1
]}

Aiden, Erez Lieberman ^{[1
,4
,5
,6
,7
,8
]}

Lander, Eric S. ^{[1
,2
,3
]}

Engreitz, Jesse M. ^{[1
,9
]}

机构：

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

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

[3] MIT, Dept Biol, Cambridge, MA 02139 USA

[4] Baylor Coll Med, Ctr Genome Architecture, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[6] Rice Univ, Dept Comp Sci, Houston, TX USA

[7] Rice Univ, Dept Computat & Appl Math, Houston, TX USA

[8] Rice Univ, Ctr Theoret Biol Phys, Houston, TX USA

[9] Harvard Univ, Harvard Soc Fellows, Cambridge, MA 02138 USA

来源：

NATURE GENETICS | 2019年 / 51卷 / 12期

关键词：

SUPER-ENHANCERS; TRANSCRIPTION; ELEMENTS; GENOME; INTERROGATION; EXPRESSION; EPIGENOME; CELLS; DISSECTION; SINGLE;

D O I：

10.1038/s41588-019-0538-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Enhancer elements in the human genome control how genes are expressed in specific cell types and harbor thousands of genetic variants that influence risk for common diseases(1-4). Yet, we still do not know how enhancers regulate specific genes, and we lack general rules to predict enhancer-gene connections across cell types(5,6). We developed an experimental approach, CRISPRi-FlowFISH, to perturb enhancers in the genome, and we applied it to test >3,500 potential enhancer-gene connections for 30 genes. We found that a simple activity-by-contact model substantially outperformed previous methods at predicting the complex connections in our CRISPR dataset. This activity-by-contact model allows us to construct genome-wide maps of enhancer-gene connections in a given cell type, on the basis of chromatin state measurements. Together, CRISPRi-FlowFISH and the activity-by-contact model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.

引用

页码：1664 / +

页数：12

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