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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.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001002268 Illumina HiSeq 2000 53
EGAD00001002657 Illumina HiSeq 2000 8
EGAD00001003106 Illumina HiSeq 2000 16
Publications Citations
Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.
Cell 167: 2016 1369-1384.e19
Chromosome contacts in activated T cells identify autoimmune disease candidate genes.
Genome Biol 18: 2017 165
Genome-wide analysis reveals no evidence of trans chromosomal regulation of mammalian immune development.
PLoS Genet 14: 2018 e1007431
Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.
Nat Commun 10: 2019 3615
An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics.
Blood Cancer J 10: 2020 101
3D reconstruction of genomic regions from sparse interaction data.
NAR Genom Bioinform 3: 2021 lqab017
Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease.
Nat Commun 12: 2021 2298
Algorithmic considerations when analysing capture Hi-C data.
Wellcome Open Res 5: 2020 289
Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution.
Nat Commun 14: 2023 268