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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 publication

DOI

10.1016/j.cell.2016.09.037

Type

Journal article

Journal

Cell

Publication Date

17/11/2016

Volume

167

Pages

1369 - 1384.e19

Keywords

chromosome conformation, disease gene prioritization, gene regulation, non-coding genetic variation, promoter capture Hi-C, Blood Cells, Cell Lineage, Cell Separation, Chromatin, Disease, Enhancer Elements, Genetic, Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematopoiesis, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci