CHU Sainte-Justine Research Centre, Montreal, Canada; Department of Psychiatry, University of Montreal, Montreal, Canada; Department of Psychology, Concordia University, Montreal, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Psychoneuroendocrinology. 2018 Nov;97:196-205. doi: 10.1016/j.psyneuen.2018.07.019. Epub 2018 Jul 27.
Environmental factors can influence gene expression via epigenetic modifications such as DNA methylation. DNA methylation levels of regulatory regions in Hypothalamo-Pituitary-Adrenal (HPA) axis-related genes assessed from brain tissues as well as from surrogate, peripheral tissues have been associated with vulnerability to stress-related psychopathologies. Commonly used peripheral samples to assess DNA methylation in living humans are derived from blood, saliva or buccal cells. Although psychiatric epigenetic studies are increasingly relying on peripheral measures of DNA methylation, it is still unknown to what extent methylation patterns across peripheral tissues are associated with each other and with measures of brain processes and behavioural stress. In the present study, with a sample of 51 healthy adults, we assessed cross-tissue correlations of DNA methylation patterns in the glucocorticoid receptor (NR3C1) 1 F promoter and the FK506 Binding Protein 5 (FKBP5) gene intron 7 region using saliva and buccal cell samples, and assessed two-year stability in both tissues in a male subsample (N = 14). We also investigated associations between peripherally-derived DNA methylation and measures of neural function and perceived daily stress, and compared the extent of these associations across tissue samples. DNA methylation cross-tissue correlations were highly significant for FKBP5, but not significant for NR3C1. DNA methylation in both genes remained stable for two years. Tissue- and gene-specific associations were found for brain resting state connectivity and neural responses to sadness, thereby suggesting that saliva- and buccal cell-derived DNA methylation levels of NR3C1-1 F and FKBP5 gene regions might differently capture different measures of putatively related brain processes. It was also found that greater buccal cell- (but not saliva-) derived NR3C1-1 F methylation was associated with lower perceived daily life demands. Results of the present study may inform the design of future epigenetic studies on FKBP5-intron-7 and NR3C1-1 F-promoter methylation in relation to neuro-imaging and behavioural measures, and provide insight for the development of peripheral DNA methylation correlates of stress sensitivity and resilience.
环境因素可以通过表观遗传修饰（如 DNA 甲基化）影响基因表达。从脑组织以及替代的外周组织评估的下丘脑-垂体-肾上腺 (HPA) 轴相关基因的调节区域的 DNA 甲基化水平与应激相关精神病理学的易感性有关。通常用于评估活体人类 DNA 甲基化的外周样本来自血液、唾液或口腔细胞。尽管精神科表观遗传学研究越来越依赖于外周 DNA 甲基化测量，但仍不清楚外周组织之间的甲基化模式彼此之间以及与大脑过程和行为应激的测量有多大程度的关联。在本研究中，我们使用 51 名健康成年人的样本，使用唾液和口腔细胞样本评估了糖皮质激素受体 (NR3C1) 1F 启动子和 FK506 结合蛋白 5 (FKBP5) 基因内含子 7 区域的 DNA 甲基化模式的跨组织相关性，并在男性亚样本中评估了两种组织的两年稳定性 (N=14)。我们还研究了外周 DNA 甲基化与神经功能和感知日常压力测量之间的关联，并比较了跨组织样本的这些关联的程度。FKBP5 的 DNA 甲基化跨组织相关性高度显著，但 NR3C1 则不显著。两种基因的 DNA 甲基化在两年内保持稳定。发现了与大脑静息状态连通性和对悲伤的神经反应相关的组织和基因特异性关联，从而表明 NR3C1-1F 和 FKBP5 基因区域的唾液和口腔细胞衍生的 DNA 甲基化水平可能以不同的方式捕获不同的与大脑过程相关的测量值。还发现，口腔细胞衍生的 NR3C1-1F 甲基化水平（而非唾液衍生的 NR3C1-1F 甲基化水平）与感知到的日常生活需求较低有关。本研究的结果可能为 FKBP5 内含子 7 和 NR3C1-1F 启动子甲基化与神经影像学和行为测量相关的未来表观遗传学研究提供信息，并为开发应激敏感性和弹性的外周 DNA 甲基化相关性提供见解。
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