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

Biola M. Javierre, Sven Sewitz, Jonathan Cairns, Steven W. Wingett, Csilla Várnai, Michiel J. Thiecke, Paula Freire-Pritchett, Mikhail Spivakov, Peter Fraser, Oliver S. Burren, Antony J. Cutler, John A. Todd, Chris Wallace, Steven P. Wilder, Roman Kreuzhuber, Myrto Kostadima, Daniel R. Zerbino, Oliver Stegle, Frances Burden, Samantha FarrowKarola Rehnström, Kate Downes, Luigi Grassi, Willem H. Ouwehand, Mattia Frontini, Steven M. Hill, Fan Wang, Hendrik G. Stunnenberg, Joost H. Martens, Bowon Kim, Nilofar Sharifi, Eva M. Janssen-Megens, Marie Laure Yaspo, Matthias Linser, Alexander Kovacsovics, Laura Clarke, David Richardson, Avik Datta, Paul Flicek

Research output: Contribution to journalArticlepeer-review

620 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1369-1384.e19
Issue number5
Publication statusPublished - 17 Nov 2016
Externally publishedYes


  • chromosome conformation
  • disease gene prioritization
  • gene regulation
  • non-coding genetic variation
  • promoter capture Hi-C


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