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

Author

Listed:
  • Stephen Watt

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Louella Vasquez

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Klaudia Walter

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Alice L. Mann

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Kousik Kundu

    (Human Genetics, Wellcome Sanger Institute, Genome Campus
    University of Cambridge)

  • Lu Chen

    (Human Genetics, Wellcome Sanger Institute, Genome Campus
    University of Cambridge
    West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University)

  • Ying Sims

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Simone Ecker

    (UCL Cancer Institute)

  • Frances Burden

    (University of Cambridge
    National Health Service Blood and Transplant (NHSBT))

  • Samantha Farrow

    (University of Cambridge
    National Health Service Blood and Transplant (NHSBT))

  • Ben Farr

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Valentina Iotchkova

    (Human Genetics, Wellcome Sanger Institute, Genome Campus
    European Bioinformatics Institute
    University of Oxford, John Radcliffe Hospital, Headington)

  • Heather Elding

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Daniel Mead

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Manuel Tardaguila

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • Hannes Ponstingl

    (Human Genetics, Wellcome Sanger Institute, Genome Campus)

  • David Richardson

    (European Bioinformatics Institute)

  • Avik Datta

    (European Bioinformatics Institute)

  • Paul Flicek

    (European Bioinformatics Institute)

  • Laura Clarke

    (European Bioinformatics Institute)

  • Kate Downes

    (University of Cambridge
    National Health Service Blood and Transplant (NHSBT))

  • Tomi Pastinen

    (Center for Pediatric Genomic Medicine, Children’s Mercy)

  • Peter Fraser

    (Babraham Institute
    Florida State University)

  • Mattia Frontini

    (University of Cambridge
    National Health Service Blood and Transplant (NHSBT)
    Addenbrooke’s Hospital
    University of Exeter Medical School, RILD Building)

  • Biola-Maria Javierre

    (Babraham Institute
    Josep Carreras Leukaemia Research Institute)

  • Mikhail Spivakov

    (Babraham Institute
    MRC London Institute of Medical Sciences (LMS)
    Imperial College Faculty of Medicine)

  • Nicole Soranzo

    (Human Genetics, Wellcome Sanger Institute, Genome Campus
    University of Cambridge)

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.

Suggested Citation

  • Stephen Watt & Louella Vasquez & Klaudia Walter & Alice L. Mann & Kousik Kundu & Lu Chen & Ying Sims & Simone Ecker & Frances Burden & Samantha Farrow & Ben Farr & Valentina Iotchkova & Heather Elding, 2021. "Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22548-8
    DOI: 10.1038/s41467-021-22548-8
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    Cited by:

    1. Laureano Tomás-Daza & Llorenç Rovirosa & Paula López-Martí & Andrea Nieto-Aliseda & François Serra & Ainoa Planas-Riverola & Oscar Molina & Rebecca McDonald & Cedric Ghevaert & Esther Cuatrecasas & Do, 2023. "Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Sourya Bhattacharyya & Ferhat Ay, 2024. "Identifying genetic variants associated with chromatin looping and genome function," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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