Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters

作者：Biola M. Javierre, Oliver S. Burren, Steven P. Wilder, Roman Kreuzhuber, Steven M. Hill, Sven Sewitz, Jonathan Cairns, Steven Wingett, Csilla Várnai, Michiel J. Thiecke, Frances Burden, Samantha Farrow, Antony J. Cutler, Karola Rehnström, Kate Downes, Luigi Grassi, Myrto Kostadima, Paula Freire-Pritchett, Fan Wang, Joost H.A. Martens, Bowon Kim, Nilofar Sharifi, Eva M. Janssen‐Megens, Marie‐Laure Yaspo, Matthias Linser, Alexander Kovacsovics, Laura Clarke, David Richardson, Avik Datta, Paul Flicek, Hendrik G. Stunnenberg, John A. Todd, Daniel R. Zerbino, Oliver Stegle, Willem H. Ouwehand, Mattia Frontini, Chris Wallace, Mikhail Spivakov, Peter Fraser · 发表于：Cell · 年份：2016 · DOI：10.1016/j.cell.2016.09.037 · 被引用次数：1197 · 研究领域：Genomics and Chromatin Dynamics、Genomic variations and chromosomal abnormalities、Bioinformatics and Genomic Networks

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.