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

Autor: Hannes Ponstingl, Simone Ecker, Manuel Tardaguila, Samantha Farrow, Paul Flicek, Valentina Iotchkova, Ben Farr, Mattia Frontini, Lu Chen, Nicole Soranzo, Louella Vasquez, Peter Fraser, David J. Richardson, Alice L. Mann, Avik Datta, Daniel Mead, Heather Elding, Kate Downes, Klaudia Walter, Tomi Pastinen, Kousik Kundu, Biola-Maria Javierre, Mikhail Spivakov, Ying Sims, Stephen Watt, Frances Burden, Laura Clarke
Přispěvatelé: Walter, Klaudia [0000-0003-4448-0301], Kundu, Kousik [0000-0002-1019-8351], Ecker, Simone [0000-0001-5648-1710], Iotchkova, Valentina [0000-0001-5057-0210], Mead, Daniel [0000-0001-7717-4330], Ponstingl, Hannes [0000-0001-7573-1703], Richardson, David [0000-0003-0247-9118], Flicek, Paul [0000-0002-3897-7955], Clarke, Laura [0000-0002-5989-6898], Fraser, Peter [0000-0002-0041-1227], Javierre, Biola-Maria [0000-0002-8682-6748], Spivakov, Mikhail [0000-0002-0383-3943], Soranzo, Nicole [0000-0003-1095-3852], Apollo - University of Cambridge Repository
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Neutrophils
45/43
General Physics and Astronomy
631/250/262
0302 clinical medicine
Transcriptional regulation
Promoter Regions
Genetic
Innate immunity
Multidisciplinary
article
49/39
Middle Aged
Acquired immune system
Chromatin
Cell biology
Enhancer Elements
Genetic
Chromatin Immunoprecipitation Sequencing
Female
Adult
Science
Quantitative Trait Loci
Biology
Chromatin structure
General Biochemistry
Genetics and Molecular Biology
Autoimmune Diseases
03 medical and health sciences
Young Adult
Immune system
Proto-Oncogene Proteins
631/208/200
medicine
Humans
Enhancer
Gene
Aged
45/91
Autoimmune disease
Innate immune system
General Chemistry
631/337/100/101
medicine.disease
Gene regulation
631/208/199
030104 developmental biology
Gene Expression Regulation
Trans-Activators
Gene expression
38/15
030217 neurology & neurosurgery
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021)
Nature Communications
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
instname
ISSN: 2041-1723
Popis: Funder: MS is funded by Medical Research Council (MC-A652-5QA20)
Funder: This work was supported by the Wellcome Trust grant (206194) and EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510)
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.
Databáze: OpenAIRE
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