title: Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.
abstract: 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.
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Biola M
authors.initials: BM
authors.lastname: Javierre
authors.affiliation: 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.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Burren
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Kreuzhuber
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Sven
authors.initials: S
authors.lastname: Sewitz
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cairns
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Wingett
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Csilla
authors.initials: C
authors.lastname: Várnai
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Michiel J
authors.initials: MJ
authors.lastname: Thiecke
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Burden
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Farrow
authors.affiliation: 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.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Grassi
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
authors.forename: Myrto
authors.initials: M
authors.lastname: Kostadima
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Freire-Pritchett
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein Zuid 30, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Zerbino
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Electronic address: mf471@cam.ac.uk.
authors.forename: Mattia
authors.initials: M
authors.lastname: Frontini
authors.affiliation: 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; MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0SP, UK. Electronic address: cew54@medschl.cam.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: mikhail.spivakov@babraham.ac.uk.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Spivakov
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: peter.fraser@babraham.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Fraser
mesh_terms: D001773:Blood Cells / Q000166:cytology*; D019070:Cell Lineage; D002469:Cell Separation; D002843:Chromatin; D004194:Disease / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D057890:Epigenomics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006410:Hematopoiesis; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci
chemical_list: D002843:Chromatin
keywords: chromosome conformation; disease gene prioritization; gene regulation; non-coding genetic variation; promoter capture Hi-C