Journal Article

Long-term DNA methylation changes mediate heterologous cytokine responses after BCG vaccination

Debisarun, Priya A., Mourits, Vera P., Li, Wenchao, Qi, Cancan, Liu, Zhaoli, Kilic, Gizem, Mekonnen, Yonatan Ayalew, Petkoglou, Apostolos, Alaswad, Ahmed, Koeken, Valerie A. C. M., Joosten, Leo A. B., Netea, Mihai G., Moorlag, Simone J. C. F. M., Sarlea, Andrei S., Liu, Xuan, de Bree, L. Charlotte J., Grasshoff, Martin, Xu, Cheng-Jian, Li, Yang

2025

Overview

Background Epigenetic reprogramming shapes immune memory in both innate (trained immunity) and adaptive immune cells following Bacillus Calmette-Guérin (BCG) vaccination. However, the role of dynamic DNA methylation changes in post-vaccination immune responses remains unclear. Results We established a cohort of 284 healthy Dutch individuals, profiling genome-wide DNA methylation and cytokine responses to ex vivo stimulation at baseline, 14 days, and 90 days post-BCG vaccination. We identified distinct patterns of DNA methylation alternations in the short- and long-term following BCG vaccination. Moreover, we established that baseline DNA methylation profiles exert influence on the change in interferon-γ (IFN-γ) production upon heterologous ( Staphylococcus aureus ) stimulation before and after BCG vaccination. Specifically, we identified the regulation of kisspeptin as a novel pathway implicated in the modulation of IFN-γ production, and this finding has been substantiated through experimental validation. We also observed associations between BCG-induced DNA methylation changes and increased IFN-γ and interleukin-1 β (IL-1β) production upon S. aureus stimulation. Interestingly, by integrating with genetic, epigenetic, and cytokine response data from the same individuals, mediation analysis demonstrated that most of the identified DNA methylation changes played a mediating role between genetic variants and cytokine responses; for example, the changes of cg21375332 near SLC12 A3 gene mediated the regulation of genetic variants on IFN-γ changes after BCG vaccination. Sex-specific effects were observed in DNA methylation and cytokine responses, highlighting the importance of considering sex in immune studies. Conclusions These findings provide deeper insights into immune response mechanisms, crucial for developing effective epigenetic-based medical interventions for personalized medicine.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: A3 gene / Adult / Animal Genetics and Genomics / Bacillus Calmette-Guerin vaccine / BCG / BCG vaccination / BCG Vaccine - administration & dosage / BCG Vaccine - immunology / Bioinformatics / Biomedical and Life Sciences / Body mass index / Cytokines / Cytokines - metabolism / Cytokines response / DNA fingerprinting / DNA Methylation / Epigenesis, Genetic / Epigenetics / Evolutionary Biology / Female / genes / Genetic diversity / Genomes / Human Genetics / Humans / Immune response / Immunity (Disease) / Immunoglobulins / immunologic memory / Immunological memory / Immunology / Infections / Interferon-gamma - genetics / Interferon-gamma - metabolism / Interleukin 1 / Interleukin-1beta / Kiss1 protein / kisspeptin / Life Sciences / Male / Metabolites / Microbial Genetics and Genomics / Middle Aged / Mycobacterium bovis BCG / Neutrophils / Pathogens / Plant Genetics and Genomics / Precision medicine / Proteins / Staphylococcus aureus / Staphylococcus aureus - immunology / Systems biology / Trained immunity / Tumor necrosis factor-TNF / Vaccination / γ-Interferon