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Cited by 63Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyNeutrophil, Myeloperoxidase and Oxidative Mechanisms

Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

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Watt, Stephen, Vasquez, Louella, Walter, Klaudia, Mann, Alice L., Kundu, Kousik, Chen, Lu, Sims, Ying, Ecker, Simone +19 more·2021·Nature Communications
DOI 10.1038/s41467-021-22548-8PMC PMC8052402
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Abstract

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.

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  • Genetic variants associated with differential binding of PU.1 underpin GWAS variants associated with blood cell count and autoimmune diseases.

    “For example, genetic variants associated with differential binding of PU.1 were found to underpin GWAS variants associated with blood cell count and autoimmune diseases [213–215].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [215]

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Cited by

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Authors
Watt, S., Vasquez, L., Walter, K., Mann, A. L., Kundu, K., Chen, L., Sims, Y., Ecker, S., Burden, F., Farrow, S., Farr, B., Iotchkova, V., Elding, H., Mead, D., Tardaguila, M., Ponstingl, H., Richardson, D., Datta, A., Flicek, P., Clarke, L., Downes, K., Pastinen, T., Fraser, P., Frontini, M., Javierre, B.-M., Spivakov, M., & Soranzo, N.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • University College London (GB)
  • National Health Service (GB)
  • European Bioinformatics Institute (GB)
  • Children's Mercy Hospital (US)
  • Florida State University (US)
  • Babraham Institute (GB)
Corresponding author
  • Javierre, Biola-Maria
  • Spivakov, Mikhail
  • Soranzo, Nicole
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-16
Volume
12
Issue
1
Pages
2298-2298
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-22548-8
PMC
PMC8052402
OpenAlex
W3154950137
Cited by
63
References
16
Citations by year
2026: 6 · 2025: 7 · 2024: 24 · 2023: 10 · 2022: 13 · 2021: 3
FWCI
4.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo
  • Apollo (cc-by)
Funders
  • Wellcome Trust (108749/Z/15/Z, /Z/15/Z, 206194, BRC-1215-20014, 098051, 108749)
  • European Molecular Biology Laboratory
  • National Institute for Health and Care Research ([IS-BRC-1215-20014, BRC1215-20014)
  • British Heart Foundation (FS/18/53/33863)
  • Department of Health and Social Care
  • European Commission (282510)
  • Ministerio de Ciencia e Innovación
  • Medical Research Council (MC-A652-5QA20, 098051, BRC-1215-20014)
  • NIHR Cambridge Biomedical Research Centre ((BRC-1215-20014), 1215-20014, BRC-1215)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
PU.1, neutrophils, enhancer-promoter interactions, chromatin looping, transcription factor binding, autoimmune disease susceptibility, inflammatory diseases, gene expression regulation, immune traits, genetic variants
MeSH terms
Chromatin Immunoprecipitation Sequencing, Proto-Oncogene Protein Spi-1, Adult, Aged, Autoimmune Diseases, Chromatin, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Neutrophils, Promoter Regions, Genetic, Proto-Oncogene Proteins, Trans-Activators, Quantitative Trait Loci, Young Adult

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