Lineage-specific genome architecture links disease variants to target genes

Long-range interactions between DNA regulatory elements and their target genes play major roles in gene regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary haematopoietic cell types. We show that long-range promoter interactions are highly cell-type specific, preferentially linking active promoters and enhancers. Patterns of promoter interactions reflect cell lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched for expression quantitative trait loci with effects on their interacting target genes. We exploit this rich resource of interactome maps to connect non-coding disease variants to their target promoters, identifying thousands of new disease-candidate genes, and implicating a number of gene pathways in disease susceptibility. Our results demonstrate the power of promoter interactomes from primary cells to reveal insights into genomic regulatory mechanisms underlying common diseases.EGA study EGAS00001001911

DNA调控元件与其靶基因之间的远程相互作用，在基因调控中发挥核心作用。目前绝大多数此类相互作用尚未被解析，这成为解析基因组调控机制的关键缺失环节。本研究采用启动子捕获Hi-C（promoter capture Hi-C）技术，在17种人类原代造血细胞类型中，对31253个启动子的相互作用区域进行了鉴定。研究发现，远程启动子相互作用具有高度的细胞类型特异性，优先连接活跃的启动子与增强子。启动子相互作用模式能够反映造血谱系树的细胞亲缘关系，与细胞分化过程中核架构的动态重塑相一致。相互作用区域显著富集对其靶基因具有调控效应的表达数量性状基因座（expression quantitative trait loci）。本研究借助这份丰富的相互作用组图谱资源，将非编码疾病变异与其靶启动子相关联，鉴定出数千个全新的疾病候选基因，并揭示了多条与疾病易感性相关的基因通路。本研究结果证实，利用原代细胞获取的启动子相互作用组，能够为解析常见疾病背后的基因组调控机制提供重要见解。EGA研究 EGAS00001001911