Institute of Immunology, Centre de Recherche Public de la Santé, Laboratoire National de Santé, 20A rue Auguste Lumière, L-1950 Luxembourg, Luxembourg; Department of Immunology, Research Institute of Psychobiology, University of Trier, D-54290 Trier, Germany.
J Psychiatr Res. 2013 Nov;47(11):1597-607. doi: 10.1016/j.jpsychires.2013.07.022. Epub 2013 Aug 12.
Glucocorticoids and the glucocorticoid (GR) and mineralocorticoid (MR) receptors have been implicated in many processes, particularly in negative feedback regulation of the hypothalamic-pituitary-adrenal axis. Epigenetically programmed GR alternative promoter usage underlies transcriptional control of GR levels, generation of GR 3' splice variants, and the overall GC response in the brain. No detailed analysis of GR first exons or GR transcript variants throughout the human brain has been reported. Therefore we investigated post mortem tissues from 28 brain regions of 5 individuals. GR first exons were expressed throughout the healthy human brain with no region-specific usage patterns. First exon levels were highly inter-correlated suggesting that they are co-regulated. GR 3' splice variants (GRα and GR-P) were equally distributed in all regions, and GRβ expression was always low. GR/MR ratios showed significant differences between the 28 tissues with the highest ratio in the pituitary gland. Modification levels of individual CpG dinucleotides, including 5-mC and 5-hmC, in promoters 1D, 1E, 1F, and 1H were low, and diffusely clustered; despite significant heterogeneity between the donors. In agreement with this clustering, sum modification levels rather than individual CpG modifications correlated with GR expression. Two-way ANOVA showed that this sum modification was both promoter and brain region specific, but that there was however no promoter*tissue interaction. The heterogeneity between donors may however hide such an interaction. In both promoters 1F and 1H modification levels correlated with GRα expression suggesting that 5-mC and 5-hmC play an important role in fine tuning GR expression levels throughout the brain.
糖皮质激素及其受体（GR 和 MR）参与了许多过程，特别是在下丘脑-垂体-肾上腺轴的负反馈调节中。GR 替代启动子的表观遗传编程是 GR 水平转录调控、GR3'剪接变异体产生和大脑中整体 GC 反应的基础。目前还没有关于整个大脑中 GR 第一外显子或 GR 转录变体的详细分析报告。因此，我们对 5 名个体的 28 个大脑区域的死后组织进行了研究。GR 第一外显子在健康的人类大脑中均有表达，没有特定区域的使用模式。第一外显子水平高度相关，表明它们受到共同调控。GR3'剪接变异体（GRα和 GR-P）在所有区域均匀分布，而 GRβ表达始终较低。GR/MR 比值在 28 种组织之间存在显著差异，其中垂体中的比值最高。包括 5-mC 和 5-hmC 在内的单个 CpG 二核苷酸在启动子 1D、1E、1F 和 1H 中的修饰水平较低，且呈弥散性聚集；尽管供体之间存在显著异质性。这种聚类与以下结果一致，即修饰水平总和而不是单个 CpG 修饰与 GR 表达相关。双因素方差分析显示，这种总和修饰具有启动子和脑区特异性，但启动子-组织间没有相互作用。然而，供体之间的异质性可能隐藏了这种相互作用。在启动子 1F 和 1H 中，修饰水平与 GRα表达相关，表明 5-mC 和 5-hmC 在整个大脑中精细调节 GR 表达水平方面发挥着重要作用。
