机构：[1]Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, UK[2]School of Clinical Medicine, University of Cambridge, Cambridge, UK[3]UCLCancer Institute, London, UK[4]Department of Haematology, University of Cambridge, Cambridge, UK[5]National Health Service Blood and Transplant(NHSBT), Cambridge, UK[6]European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK[7]Center for Pediatric Genomic Medicine, Children’s Mercy, Kansas City, MO, USA[8]Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK[9]British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK[10]Josep Carreras Leukaemia ResearchInstitute, Badalona, Barcelona, Spain[11]Functional Gene Control Group, MRC London Institute of Medical Sciences (LMS), London, UK[12]Institute of Clinical Sciences, Imperial College Faculty of Medicine, London, UK[13]Key Laboratory of Birth Defects and Related Diseases of Women and Children,Department of Laboratory Medicine, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China[14]MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital,Headington, Oxford, UK[15]Department of Biological Science, Florida State University, Tallahassee, FL, USA[16]Institute of Biomedical & Clinical Science, College of Medicine and Health, University of Exeter Medical School, RILD Building, Exeter, UK
Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.
基金：
This work was supported by the Wellcome Trust grant reference (098051,
206194 and 108749/Z/15/Z), EU-FP7 Project BLUEPRINT (HEALTH-F5-2011-282510).
This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-
1215-20014).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
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第一作者：
第一作者机构：[1]Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, UK
通讯作者：
通讯机构：[1]Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, UK[2]School of Clinical Medicine, University of Cambridge, Cambridge, UK[8]Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK[10]Josep Carreras Leukaemia ResearchInstitute, Badalona, Barcelona, Spain[11]Functional Gene Control Group, MRC London Institute of Medical Sciences (LMS), London, UK[12]Institute of Clinical Sciences, Imperial College Faculty of Medicine, London, UK
推荐引用方式(GB/T 7714)：
Stephen Watt,Louella Vasquez,Klaudia Walter,et al.Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease.[J].Nature communications.2021,12(1):2298.doi:10.1038/s41467-021-22548-8.
APA：
Stephen Watt,Louella Vasquez,Klaudia Walter,Alice L. Mann,Kousik Kundu...&Nicole Soranzo.(2021).Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease..Nature communications,12,(1)
MLA：
Stephen Watt,et al."Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease.".Nature communications 12..1(2021):2298
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