Activity-by-contact Model of Enhancer-promoter Regulation from Thousands of CRISPR Perturbations

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Dec 1

PMID 31784727

Citations 481

Authors

Charles P Fulco

Joseph Nasser

Thouis R Jones

Glen Munson

Drew T Bergman

Vidya Subramanian

Sharon R Grossman

Rockwell Anyoha

Benjamin R Doughty

Tejal A Patwardhan

Tung H Nguyen

Michael Kane

Elizabeth M Perez

Neva C Durand

Caleb A Lareau

Elena K Stamenova

Erez Lieberman Aiden

Eric S Lander

Jesse M Engreitz

Affiliations

Soon will be listed here.

Abstract

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. Yet, we still do not know how enhancers regulate specific genes, and we lack general rules to predict enhancer-gene connections across cell types. 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.

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