Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease
Stephen M. Watt, Louella Vasquez, Klaudia Walter, Alice Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben W. Farr, Valentina Iotchkova, Heather Elding, Daniel G. Mead, Manuel Tardáguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola M. Javierre, Mikhail Spivakov, Nicole Soranzo
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.