HPA axis regulation and epigenetic programming of immune-related genes in chronically stressed and non-stressed mid-life women.
HPA axis regulation and epigenetic programming of immune-related genes in chronically stressed and non-stressed mid-life women.
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DOI：
10.1016/j.bbi.2020.11.027
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Zannas AS
中科院分区：
文献类型：
--
作者：
Palma-Gudiel H;Prather AA;Lin J;Oxendine JD;Guintivano J;Xia K;Rubinow DR;Wolkowitz O;Epel ES;Zannas AS
下丘脑-垂体-肾上腺(HPA)轴失调与免疫功能改变有关，但其潜在的分子机制尚不清楚。表观遗传过程，包括DNA甲基化，对HPA轴的糖皮质激素终产物(人类的皮质醇)做出反应，并可能参与这种神经内分泌-免疫串扰。在这里，我们研究了57名长期应激照顾者和67名对照妇女的HPA轴调节变化与外周血DNA(CpG)甲基化变化的关系。用Illumina 450k芯片检测与HPA轴和免疫功能相关的一组基因的DNA甲基化。用小剂量地塞米松抑制试验(DST)评估HPA轴反馈，测量合成的糖皮质激素地塞米松对皮质醇分泌的抑制程度。在对整个队列进行多次测试校正后，反映钝化HPA轴负反馈的DST后较高的皮质醇，而不是基线唤醒的皮质醇，与8个TNF和2个FKBP5 CpG处较低的DNA甲基化有关。照顾者群体状态与IL6 CpG两个位点的甲基化程度较低相关。由于与肿瘤坏死因子甲基化的相关性最强(450k覆盖的位点中有32%)，我们进一步在33名参与者的外周血单核细胞中检测了这种表观遗传特征的功能性；有趣的是，较低的肿瘤坏死因子甲基化导致免疫刺激后体外肿瘤坏死因子信使核糖核酸增加。综上所述，我们的发现将慢性应激和HPA轴调节与免疫相关基因的表观遗传特征联系起来，从而为HPA轴功能异常如何导致炎症和疾病风险增加提供了新的见解。
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.
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影响因子：
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作者：
COHEN, S;KAMARCK, T;MERMELSTEIN, R
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