An integrative genomics approach identifies KDM4 as a modulator of trained immunity
Publication year
2022Author(s)
Source
European Journal of Immunology, 52, 3, (2022), pp. 431-446ISSN
Publication type
Article / Letter to editor

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Organization
Internal Medicine
Health Evidence
Surgery
Haematology
Human Genetics
Journal title
European Journal of Immunology
Volume
vol. 52
Issue
iss. 3
Page start
p. 431
Page end
p. 446
Subject
Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 16: Vascular damage RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life SciencesAbstract
Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.
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- Academic publications [234109]
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- Faculty of Medical Sciences [89175]
- Open Access publications [83945]
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