Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-22548-8
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Funding
- Wellcome Trust [098051, 206194, 108749/Z/15/Z]
- EU-FP7 Project BLUEPRINT [HEALTH-F5-2011-282510]
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- Medical Research Council of the UK as an MRC Investigator [MC-A652-5QA20]
- FEDER/Spanish Ministry of Science and Innovation [RTI2018-094788-A-I00]
- La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]
- European Molecular Biology Laboratory
- Wellcome Trust [108749/Z/15/Z] Funding Source: Wellcome Trust
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Genetic variants affecting PU.1 binding are associated with differences in neutrophil count and susceptibility to autoimmune and inflammatory diseases, shedding light on the pathogenesis of immune-related disorders.
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. PU.1 is a master regulator of myeloid development but its role in disease-relevant neutrophils is not well known. Here, the authors look at primary neutrophils from a human population and find that genetic variants affecting binding of PU.1 are associated with cell count and disease susceptibility.
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