Javierre Biola M, Burren Oliver S, Wilder Steven P, Kreuzhuber Roman, Hill Steven M, Sewitz Sven, Cairns Jonathan, Wingett Steven W, Várnai Csilla, Thiecke Michiel J, Burden Frances, Farrow Samantha, Cutler Antony J, Rehnström Karola, Downes Kate, Grassi Luigi, Kostadima Myrto, Freire-Pritchett Paula, Wang Fan, Stunnenberg Hendrik G, Todd John A, Zerbino Daniel R, Stegle Oliver, Ouwehand Willem H, Frontini Mattia, Wallace Chris, Spivakov Mikhail, Fraser Peter
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
Cell. 2016 Nov 17;167(5):1369-1384.e19. doi: 10.1016/j.cell.2016.09.037.
Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional 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 hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.
调控元件与基因启动子之间的远程相互作用在转录调控中起着关键作用。绝大多数相互作用尚未被探索，这是理解基因组控制方面的一个主要缺失环节。在这里，我们使用启动子捕获Hi-C技术来鉴定17种人类原代造血细胞类型中31253个启动子的相互作用区域。我们发现启动子相互作用具有高度的细胞类型特异性，并且在活性启动子与表观遗传标记的增强子之间的联系中富集。启动子相互作用组反映了造血树的谱系关系，这与分化过程中核结构的动态重塑相一致。相互作用区域富集了与其接触的基因表达改变相关的遗传变异，突出了它们的功能作用。我们利用这一丰富资源将非编码疾病变异与假定的靶启动子联系起来，对数千个疾病候选基因进行优先级排序，并揭示疾病途径。我们的结果证明了原代细胞启动子相互作用组在揭示常见疾病潜在基因组调控机制方面的强大作用。
