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

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, 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 () and Nicole Soranzo ()
Additional contact information
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
Lu Chen: Human Genetics, Wellcome Sanger Institute, Genome Campus
Ying Sims: Human Genetics, Wellcome Sanger Institute, Genome Campus
Simone Ecker: UCL Cancer Institute
Frances Burden: University of Cambridge
Samantha Farrow: University of Cambridge
Ben Farr: Human Genetics, Wellcome Sanger Institute, Genome Campus
Valentina Iotchkova: Human Genetics, Wellcome Sanger Institute, Genome Campus
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
Tomi Pastinen: Center for Pediatric Genomic Medicine, Children’s Mercy
Peter Fraser: Babraham Institute
Mattia Frontini: University of Cambridge
Biola-Maria Javierre: Babraham Institute
Mikhail Spivakov: Babraham Institute
Nicole Soranzo: Human Genetics, Wellcome Sanger Institute, Genome Campus

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22548-8

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DOI: 10.1038/s41467-021-22548-8

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