Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci (Articolo in rivista)

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  • Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1101/gr.155127.113 (literal)
Alternative label
  • Paul DS, Albers CA, Rendon A, Voss K, Stephens J; HaemGen Consortium, van der Harst P, Chambers JC, Soranzo N, Ouwehand WH, Deloukas P (2013)
    Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci
    in Genome research (Online)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Paul DS, Albers CA, Rendon A, Voss K, Stephens J; HaemGen Consortium, van der Harst P, Chambers JC, Soranzo N, Ouwehand WH, Deloukas P (literal)
Pagina inizio
  • 1130 (literal)
Pagina fine
  • 1141 (literal)
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  • http://genome.cshlp.org/content/23/7/1130.long (literal)
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  • 23 (literal)
Rivista
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  • 11 (literal)
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  • PubMe (literal)
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  • 1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; 2UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom; 3Department of Haematology, University of Cambridge and National Health Service (NHS) Blood and Transplant, Cambridge CB2 0PT, United Kingdom; 4Department of Human Genetics, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands; 5MRC Biostatistics Unit, Institute of Public Health, Cambridge CB2 0SR, United Kingdom; 6NIHR Biomedical Research Centre, Cambridge CB2 0PT, United Kingdom; 7Department of Cardiology, 8Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; 9Department of Epidemiology and Biostatistics, Imperial College London, London W2 1NY, United Kingdom; 10Imperial College Healthcare NHS Trust, Hammersmith Hospital, London W12 0HS, United Kingdom; 11Royal Brompton and Harefield Hospitals NHS Trust, London SW3 6NP, United Kingdom; 12Ealing Hospital NHS Trust, Southall, Middlesex UB1 3HW, United Kingdom 15A full list of members is provided in the Supplemental Material (literal)
Titolo
  • Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci (literal)
Abstract
  • Gli autori CNR sono inclusi tra i collaboratori all'interno del HaemGen Consortium. (literal)
  • Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. (literal)
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