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Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Yan, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo
doi: https://doi.org/10.1101/620260
Stephen Watt
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Louella Vasquez
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Klaudia Walter
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Alice L. Mann
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Kousik Kundu
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Lu Chen
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
10School of Clinical Medicine, University of Cambridge, 307 Hills Rd, Cambridge CB2 0AH, UK
11Key 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 610041, China
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Ying Yan
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Simone Ecker
2UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK
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Frances Burden
3Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
4National Health Service Blood and Transplant (NHSBT),Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
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Samantha Farrow
3Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
4National Health Service Blood and Transplant (NHSBT),Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
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Ben Farr
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Valentina Iotchkova
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
12MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
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Heather Elding
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Daniel Mead
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Manuel Tardaguila
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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Hannes Ponstingl
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
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David Richardson
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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Avik Datta
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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Paul Flicek
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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Laura Clarke
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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Kate Downes
3Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
4National Health Service Blood and Transplant (NHSBT),Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
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Tomi Pastinen
6Center for Pediatric Genomic Medicine, Children’s Mercy, 2401 Gilham Rd, Kansas City, MO, 64108, USA
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Peter Fraser
7Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK
13Department of Biological Science, Florida State University, Tallahassee, FL, USA
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Mattia Frontini
3Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
4National Health Service Blood and Transplant (NHSBT),Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
8British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
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Biola-Maria Javierre
7Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK
14Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias I Pujol, Badalona, 08916, Barcelona, Spain
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  • For correspondence: bmjavierre@carrerasresearch.org mikhail.spivakov@lms.mrc.ac.uk ns6@sanger.ac.uk
Mikhail Spivakov
7Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK
9Functional Gene Control Group, MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK
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  • For correspondence: bmjavierre@carrerasresearch.org mikhail.spivakov@lms.mrc.ac.uk ns6@sanger.ac.uk
Nicole Soranzo
1Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton CB10 1HH, UK
10School of Clinical Medicine, University of Cambridge, 307 Hills Rd, Cambridge CB2 0AH, UK
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  • For correspondence: bmjavierre@carrerasresearch.org mikhail.spivakov@lms.mrc.ac.uk ns6@sanger.ac.uk
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Abstract

Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.

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  • ↵* Joint senior authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 29, 2019.
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Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility
Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Yan, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo
bioRxiv 620260; doi: https://doi.org/10.1101/620260
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Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility
Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Yan, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo
bioRxiv 620260; doi: https://doi.org/10.1101/620260

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