与女性压力有关的 BDNF 甲基化:表观遗传学和炎症的新见解

IF 3.7 Q2 IMMUNOLOGY
Luciana Fungaro Rissatti , David Wilson , Fanny Palace-Berl , Bárbara de Mello Ponteciano , Flávia Sardela de Miranda , Ivana Alece Arantes Moreno , Tamires dos Santos Vieira , Bruna Pereira Sorroche , Lidia Maria Rebolho Batista Arantes , Adriana Madeira Alvares da Silva , Vânia D'Almeida , Marcelo Demarzo , Daniela Rodrigues de Oliveira
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引用次数: 0

摘要

脑源性神经营养因子(BDNF)基因在调节应激反应轴和炎症方面起着重要作用,可通过表观遗传机制进行调控。BNDF 甲基化与抑郁、焦虑和创伤后应激等应激相关精神疾病有关。先前的研究报告称,应激事件与 BNDF 第 IV 外显子启动子的 DNA 甲基化(DNAm)的长期改变有关,这表明糖皮质激素和炎症细胞因子可调控这一过程。我们之前发现,心理压力感知受白细胞介素(IL)-6、IL-8、IL-10 和 IL-12p70 等炎性细胞因子的调节,这表明它们在介导压力反应中发挥作用。然而,介导这种反应的表观遗传学机制尚未完全明了。在本研究中,我们提出高感知压力和高血清炎症细胞因子水平可能与 BNDF 第 IV 外显子启动子中的特定甲基化位点相关。为了解决这些问题,我们对巴西从事基础教育工作的 82 名成年女教师进行了横断面研究。我们使用感知压力量表来评估压力,并采集了血液样本,分别通过流式细胞术测定法和 DNA 高温测序法测定炎症标志物和 BNDF 甲基化。我们在 BNDF 基因中检测到了不同的 CpG 甲基化位点,其中 5 个 CpG 位点与高压力水平直接相关。然而,有4个CpG位点显示出反向效应,表明这些位点甲基化水平的变化可能会对感知压力产生保护作用。关于炎症标志物,IL-6和IL-8与高感知压力相关。然而,只有IL-8和IL-10同时显示出对感知压力的调节作用,而IL-10和IL12p70则与DNAm相关。我们发现,IL-10和IL-12p70血清水平越高,CpG11的甲基化程度越低。我们还发现 IL-12p70 与 CpG5 和 13 的甲基化有直接关系,血清中较高水平的 IL-12p70 会分别增加 CpG5 和 13 的甲基化。总的来说,我们的研究结果加强了关于 BDNF 基因中应激敏感区域的假设,主要是 CpG5、11 和 13。此外,CpG7 和 9 可被视为应激保护区。我们的数据表明,血液中的 BDNF DNAm 可能是一种新型生物标志物,可用于早期检测健康人长期暴露于压力下的不良影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
BDNF methylation associated with stress in women: Novel insights in epigenetics and inflammation
The brain-derived neurotrophic factor (BDNF) gene plays an important role in modulating the stress-response axis and inflammation, which can be regulated by epigenetic mechanisms. BNDF methylation has been associated with stress-related psychiatric disorders such as depression, anxiety and post-traumatic stress. Previous studies have reported that stressful events are involved with long-lasting alterations in DNA methylation (DNAm) of the BNDF exon IV promoter, suggesting that glucocorticoids and inflammatory cytokines can regulate this process. We previously found that perceived psychological stress is modulated by inflammatory cytokines, such as interleukin (IL)-6, IL-8 and IL-10, and IL-12p70, suggesting their role in mediating the stress response. However, the epigenetic mechanism mediating this response has yet to be fully understood. In this study, we propose that high perceived stress and high serum levels of inflammatory cytokines may correlate with specific methylation sites within the BNDF exon IV promoter. To address these questions, we conducted a cross-sectional study of 82 adult women teachers working in basic education in Brazil. The perceived stress scale was used to assess stress and blood samples were collected for the measurement of inflammatory markers and BNDF methylation through flow cytometry assay and DNA pyrosequencing, respectively. We detected differentially methylated CpG sites in the BNDF gene, where 5 CpG sites were directly correlated with high stress levels. However, 4 CpG sites showed inverse effects, indicating that changes in methylation levels in those sites could lead to a protective effect on perceived stress. About inflammatory markers, IL-6 and IL-8 were associated with high perceived stress. However, only IL-8 and IL-10 showed simultaneous modulation of perceived stress, while IL-10 and IL12p70 correlated with DNAm. We found that higher levels in IL-10 and IL-12p70 serum decrease methylation in CpG11. A direct relationship was also found to IL-12p70, where higher levels in serum increase methylation in CpG5 and 13, respectively. Taken as a whole, our findings reinforce the hypothesis regarding stress-sensitive regions within the BDNF gene, mainly for CpG5, 11, and 13. In addition to these results, CpG7 and 9 may be regarded as stress-protective regions. Our data suggest that BDNF DNAm in the blood may represent a novel biomarker for early detection of adverse effects of chronic exposure to stress in healthy individuals.
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来源期刊
Brain, behavior, & immunity - health
Brain, behavior, & immunity - health Biological Psychiatry, Behavioral Neuroscience
CiteScore
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