Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations
Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations
复制标题
DOI：
10.1038/s41588-019-0538-0
复制
发表时间：
2019-12-01
期刊：
影响因子：
30.8
通讯作者：
Engreitz, Jesse M.
中科院分区：
文献类型：
--
作者：
Fulco, Charles P.;Nasser, Joseph;Engreitz, Jesse M.
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，并含有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剂如何调控特定的基因，我们也缺乏预测不同细胞类型的增强子-基因联系的一般规则(5，6)。我们开发了一种实验方法CRISPRi-FlowFISH来干扰基因组中的增强子，并将其应用于测试30个基因的3,500个潜在的增强子-基因连接。我们发现，在我们的CRISPR数据集中，一个简单的按接触活动模型在预测复杂连接方面显著优于以前的方法。这种接触活性模型允许我们在染色质状态测量的基础上，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和接触活性模型一起提供了一种系统的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个疾病风险变体的功能。
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.