Qi Cancan, Liu Zhaoli, Kilic Gizem, Sarlea Andrei S, Debisarun Priya A, Liu Xuan, Mekonnen Yonatan Ayalew, Li Wenchao, Grasshoff Martin, Alaswad Ahmed, Petkoglou Apostolos, Koeken Valerie A C M, Moorlag Simone J C F M, de Bree L Charlotte J, Mourits Vera P, Joosten Leo A B, Li Yang, Netea Mihai G, Xu Cheng-Jian
Centre for Individualised Infection Medicine (CiiM), a joint venture between the, Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany.
TWINCORE, a joint venture between theHelmholtz-Centre for Infection Research (HZI)Hannover Medical School (MHH), Hannover, Germany.
Genome Biol. 2025 Jul 9;26(1):180. doi: 10.1186/s13059-025-03611-9.
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.
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.
These findings provide deeper insights into immune response mechanisms, crucial for developing effective epigenetic-based medical interventions for personalized medicine.
卡介苗（BCG）接种后，表观遗传重编程塑造了先天免疫细胞（训练免疫）和适应性免疫细胞中的免疫记忆。然而，动态DNA甲基化变化在接种后免疫反应中的作用仍不清楚。
我们建立了一个由284名健康荷兰人组成的队列，分析了卡介苗接种后基线、14天和90天全基因组DNA甲基化情况以及对体外刺激的细胞因子反应。我们在卡介苗接种后的短期和长期内确定了不同的DNA甲基化变化模式。此外，我们发现基线DNA甲基化谱对卡介苗接种前后异源（金黄色葡萄球菌）刺激后干扰素-γ（IFN-γ）产生的变化有影响。具体而言，我们确定了 kisspeptin 的调控是参与IFN-γ产生调节的一条新途径，这一发现已通过实验验证得到证实。我们还观察到卡介苗诱导的DNA甲基化变化与金黄色葡萄球菌刺激后IFN-γ和白细胞介素-1β（IL-1β）产生增加之间的关联。有趣的是，通过整合来自同一人群的遗传、表观遗传和细胞因子反应数据，中介分析表明，大多数已确定的DNA甲基化变化在基因变异和细胞因子反应之间起中介作用；例如，SLC12A3基因附近的cg21375332变化介导了卡介苗接种后基因变异对IFN-γ变化的调控。在DNA甲基化和细胞因子反应中观察到了性别特异性效应，突出了在免疫研究中考虑性别的重要性。
这些发现为免疫反应机制提供了更深入的见解，这对于开发基于表观遗传的有效医学干预措施以实现个性化医疗至关重要。
