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

• Published in: Nature communications Vol. 12; no. 1; p. 2298
• Main Authors: Watt, Stephen, Vasquez, Louella, Walter, Klaudia, Mann, Alice L., Kundu, Kousik, Chen, Lu, Sims, Ying, Ecker, Simone, Burden, Frances, Farrow, Samantha, Farr, Ben, Iotchkova, Valentina, Elding, Heather, Mead, Daniel, Tardaguila, Manuel, Ponstingl, Hannes, Richardson, David, Datta, Avik, Flicek, Paul, Clarke, Laura, Downes, Kate, Pastinen, Tomi, Fraser, Peter, Frontini, Mattia, Javierre, Biola-Maria, Spivakov, Mikhail, Soranzo, Nicole
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/15; 45/43; 45/91; 49/39; 631/208/199; 631/208/200; 631/250/262; 631/337/100/101; Adaptive immunity; Adult; Aged; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Binding; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation Sequencing; Disease; Disease control; Enhancer Elements, Genetic - genetics; Enhancers; Female; Gene expression; Gene Expression Regulation - immunology; Genetic diversity; Genetic variance; Human populations; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunological diseases; Inflammatory diseases; Innate immunity; Leukocytes (neutrophilic); Male; Middle Aged; multidisciplinary; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Perturbation; Population genetics; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - metabolism; PU.1 protein; Quantitative Trait Loci - genetics; Quantitative Trait Loci - immunology; Science; Science (multidisciplinary); Trans-Activators - metabolism; Transcription; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22548-8

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.