Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease
Watt, Stephen (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Vasquez, Louella (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Walter, Klaudia (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Mann, Alice L. (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Kundu, Kousik (School of Clinical Medicine. University of Cambridge)
Chen, Lu (Sichuan University)
Sims, Ying (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Ecker, Simone (UCL Cancer Institute)
Burden, Frances (National Health Service Blood and Transplant)
Farrow, Samantha (National Health Service Blood and Transplant)
Farr, Ben (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Iotchkova, Valentina (University of Oxford)
Elding, Heather (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Mead, Daniel (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Tardaguila, Manuel (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Ponstingl, Hannes (Human Genetics. Wellcome Sanger Institute. Genome Campus)
Richardson, David (European Molecular Biology Laboratory. European Bioinformatics Institute)
Datta, Avik (European Molecular Biology Laboratory. European Bioinformatics Institute)
Flicek, Paul (European Molecular Biology Laboratory. European Bioinformatics Institute)
Clarke, Laura (European Molecular Biology Laboratory. European Bioinformatics Institute)
Downes, Kate (National Health Service Blood and Transplant)
Pastinen, Tomi (Center for Pediatric Genomic Medicine. Children's Mercy)
Fraser, Peter (Florida State University)
Frontini, Mattia (University of Exeter Medical School)
Javierre, B. M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Spivakov, Mikhail (Imperial College Faculty of Medicine)
Soranzo, Nicole (University of Cambridge)

Data:	2021
Resum:	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.
Ajuts:	Ministerio de Ciencia e Innovación RTI2018-094788-A-I00
Nota:	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). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. M.S. is core-funded by the Medical Research Council of the UK as an MRC Investigator (MC-A652-5QA20). B.M.J. is funded by the FEDER/Spanish Ministry of Science and Innovation (RTI2018-094788-A-I00) and by La Caixa Banking Foundation Junior Leader project (LCF/BQ/PI19/ 11690001). D.R., A.D., L.C., and P. Flicek are supported by the European Molecular Biology Laboratory. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers. We thank the Cambridge BioResource staff for their help with volunteer recruitment. We would like to thank members of the EU Blueprint consortium including, Dirk Paul, Daniel Rico, Vera Pancaldi, Willem Ouwehand and Henk Stun-nenberg. In addition, Stephen Wingett from Babraham Institute Bioinformatics team. Members of the sequencing centres of Wellcome Sanger Institute and Babraham Institute. Lorenz Wernisch for advice on statistics.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Adult ; Aged ; Autoimmune Diseases ; Chromatin ; Chromatin Immunoprecipitation Sequencing ; Enhancer Elements, Genetic ; Female ; Gene Expression Regulation ; Humans ; Male ; Middle Aged ; Neutrophils ; Promoter Regions, Genetic ; Proto-Oncogene Proteins ; Quantitative Trait Loci ; Trans-Activators ; Young Adult
Publicat a:	Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 2298, ISSN 2041-1723

DOI: 10.1038/s41467-021-22548-8
PMID: 33863903

12 p, 1.9 MB

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