Platelet function is modified by common sequence variation in megakaryocyte super enhancers.,Nature Communications

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Platelet function is modified by common sequence variation in megakaryocyte super enhancers.
Nature Communications ( IF 14.7 ) Pub Date : 2017-07-13 , DOI: 10.1038/ncomms16058
Romina Petersen _{1,

2} , John J Lambourne _{1,

2} , Biola M Javierre ₃ , Luigi Grassi _{1,

2,

4} , Roman Kreuzhuber _{1,

2,

5} , Dace Ruklisa _{1,

2,

6} , Isabel M Rosa _{1,

2} , Ana R Tomé _{1,

2} , Heather Elding _{7,

8} , Johanna P van Geffen ₉ , Tao Jiang ₁₀ , Samantha Farrow _{1,

2} , Jonathan Cairns ₃ , Abeer M Al-Subaie _{1,

2,

11} , Sofie Ashford _{1,

2,

4} , Antony Attwood _{1,

2,

4} , Joana Batista _{1,

2} , Heleen Bouman ₇ , Frances Burden _{1,

2} , Fizzah A Choudry _{1,

2} , Laura Clarke ₅ , Paul Flicek ₅ , Stephen F Garner ₂ , Matthias Haimel _{4,

12} , Carly Kempster _{1,

2} , Vasileios Ladopoulos ₁ , An-Sofie Lenaerts _{13,

14} , Paulina M Materek _{13,

14} , Harriet McKinney _{1,

2} , Stuart Meacham _{1,

2,

4} , Daniel Mead ₇ , Magdolna Nagy ₉ , Christopher J Penkett _{1,

2,

4} , Augusto Rendon _{1,

2,

15} , Denis Seyres _{1,

2,

4} , Benjamin Sun ₁₀ , Salih Tuna _{1,

2,

4} , Marie-Elise van der Weide _{1,

2} , Steven W Wingett ₃ , Joost H Martens ₁₆ , Oliver Stegle ₅ , Sylvia Richardson ₆ , Ludovic Vallier _{14,

17} , David J Roberts _{18,

19,

20} , Kathleen Freson ₂₁ , Lorenz Wernisch ₆ , Hendrik G Stunnenberg ₁₆ , John Danesh _{7,

8,

10,

22} , Peter Fraser _{3,

23} , Nicole Soranzo _{1,

7,

8,

22} , Adam S Butterworth _{8,

10,

22} , Johan W Heemskerk ₉ , Ernest Turro _{1,

2,

4,

6} , Mikhail Spivakov ₃ , Willem H Ouwehand _{1,

2,

7,

8,

22} , William J Astle _{1,

2,

6,

10,

22} , Kate Downes _{1,

2} , Myrto Kostadima _{1,

2,

5} , Mattia Frontini _{1,

2,

22}

Affiliation

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Medical Research Council Biostatistics Unit, University of Cambridge, Forvie Site, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Strangeways Research Laboratory, The National Institute for Health Research (NIHR) Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Cambridge CB1 8RN, UK.
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
Strangeways Research Laboratory, MRC/British Heart Foundation (BHF) Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Dammam, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
NIHR Cambridge Biomedical Research Centre hIPSC Core Facility, Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK.
Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK.
Genomics England Limited, Queen Mary University of London, Dawson Hall, London EC1M 6BQ, UK.
Faculty of Science, Department of Molecular Biology, Radboud University, 6525GA Nijmegen, The Netherlands.
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX9 3DU, UK.
Department of Haematology, Churchill Hospital, Headington, Oxford OX3 7LE, UK.
NHSBT, John Radcliffe Hospital, Headington, Oxford OX3 9BQ, UK.
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium.
BHF Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Department of Biological Science, Florida State University, Tallahassee, Florida 32303, USA.

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.

中文翻译：

巨核细胞超级增强子中的常见序列变异改变了血小板功能。

将与疾病风险或疾病相关性状相关的非编码遗传变异与目标基因联系起来是实现 GWAS 在引入精准医学方面潜力的关键步骤。在这里，我们开始使用细胞类型匹配的表观基因组数据和启动子远程相互作用来确定支持变异与血小板数量性状关联的机制。我们确定了与血小板性状相关的 565 个非编码变体中的 423 个（75%）的潜在调节功能，并且我们通过离体和原理基因组编辑验证证明，超级增强子中的变体在控制原型血小板功能中起重要作用.

更新日期：2017-07-13

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