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

Stephen Watt,Lu Chen,David Richardson,Mattia Frontini,Mikhail Spivakov,Simone Ecker,Daniel G Mead ,Ben W Farr ,Manuel Tardáguila ,Biola M Javierre ,Peter Fraser,Laura Clarke,Valentina Iotchkova,Tomi Pastinen,Paul Flicek,Hannes Ponstingl,Samantha Farrow,Kate Downes,Heather Elding,Avik Datta,Louella Vasquez,Ying Sims,Alice L Mann,Kousik Kundu,Frances Burden,Klaudia Walter,Nicole Soranzo

doi:10.1038/s41467-021-22548-8

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.

Highlights

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
We generated PU.[1] chromatin immunoprecipitation sequencing (ChIP-seq) data from CD66b+CD16+ neutrophils isolated from fully genotyped individuals forming part of the BLUEPRINT project cohort[14,25], with data from a total of 93 donors passing quality control
We have identified thousands of DNA variants associated with altered PU.[1] binding, and show that they associate with downstream transcriptional regulatory events, including local chromatin state, longrange enhancer-promoter contacts and gene expression

Summary

Introduction

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. 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 multiindividual 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. These results demonstrate the functional role of PU.[1] and its target enhancers in neutrophil transcriptional control and immune disease susceptibility. Enhancer activity is associated with specific patterns of chromatin accessibility and histone modifications

Methods

Results

Conclusion