Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.,Nature Genetics

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Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.
Nature Genetics ( IF 31.7 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41588-019-0538-0
Charles P Fulco _{1,

2} , Joseph Nasser ₁ , Thouis R Jones ₁ , Glen Munson ₁ , Drew T Bergman ₁ , Vidya Subramanian ₁ , Sharon R Grossman _{1,

3} , Rockwell Anyoha ₁ , Benjamin R Doughty ₁ , Tejal A Patwardhan ₁ , Tung H Nguyen ₁ , Michael Kane ₁ , Elizabeth M Perez ₁ , Neva C Durand _{1,

4,

5,

6} , Caleb A Lareau ₁ , Elena K Stamenova ₁ , Erez Lieberman Aiden _{1,

4,

5,

6,

7} , Eric S Lander _{1,

2,

3} , Jesse M Engreitz _{1,

8}

Affiliation

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 diseases1-4. Yet, we still do not know how enhancers regulate specific genes, and we lack general rules to predict enhancer-gene connections across cell types5,6. 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.

中文翻译：

来自数千个 CRISPR 扰动的增强子-启动子调控的活性接触模型。

人类基因组中的增强子元件控制基因在特定细胞类型中的表达方式，并包含数千种影响常见疾病风险的遗传变异1-4。然而，我们仍然不知道增强子如何调节特定基因，并且我们缺乏预测跨细胞类型的增强子-基因连接的一般规则5,6。我们开发了一种实验方法 CRISPRi-FlowFISH 来扰乱基因组中的增强子，并应用它来测试 30 个基因的超过 3,500 个潜在的增强子-基因连接。我们发现，在预测 CRISPR 数据集中的复杂连接方面，简单的接触活动模型大大优于以前的方法。这种接触活动模型使我们能够根据染色质状态测量来构建给定细胞类型中增强子基因连接的全基因组图谱。 CRISPRi-FlowFISH 和接触活性模型共同提供了一种系统方法来绘制和预测哪些增强子调节哪些基因，并将有助于解释非编码基因组中数千种疾病风险变异的功能。

更新日期：2019-11-30

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