Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed
Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed
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DOI：
10.1016/j.psyneuen.2009.09.001
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发表时间：
2010-05-01
影响因子：
3.7
通讯作者：
Muller, Claude P.
中科院分区：
文献类型：
--
作者：
Alt, Simone R.;Turner, Jonathan D.;Muller, Claude P.
下丘脑-垂体-肾上腺(HPA)轴的过度活动是重度抑郁障碍(MDD)最一致的发现之一。HPA反馈受损可能是由于前脑中糖皮质激素受体(GR)或盐皮质激素受体(MR)水平降低所致。GR水平由多个未翻译的替代第一外显子转录控制，每个外显子都有自己的启动子，为GR水平的组织特异性微调提供了一种机制。最近，这些GR启动子的表观遗传甲基化被证明调节了海马GR水平。在尸检脑组织中，GRα、GRβ和GR-P的转录水平是一致的，其中GRα含量最高(83%)，其次是GR-P(5-6%)，而GR-β几乎检测不到(0.02%)。在备选的第一外显子中，1B和1C活性最高，1E和1J的表达水平最低，1F的表达水平居中。在MDD中，总GR水平没有变化，尽管GRA在杏仁核和扣带回减少(p<；0.05)；含有1B、1C和1F外显子的转录本较低，1D和1J的转录本在某些区域增加。MDD患者海马区外显子1F转录因子NGFI-A表达下调，外显子1F表达降低。亚硫酸氢盐对替代启动子的测序显示，MDD和对照组大脑中的甲基化水平都很低。启动子1F均未甲基化，这表明1F转录水平的降低与启动子甲基化无关，而与观察到的NGFI-A缺乏有关。以前的研究表明，1F启动子的甲基化水平较高，与儿童虐待有关。如果我们的捐赠者没有被虐待，我们的结果表明MDD的病理机制与虐待受害者相似，但却不同，这解释了这两种疾病的临床相似性，抑郁症的易感性可能是由早期创伤易患，也可能是独立于这种疾病发展起来的。然而，这一点应该在更大的队列中的专门研究中得到进一步证实。(C)2009爱思唯尔有限公司。保留所有权利。
Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis is one of the most consistent findings in major depressive disorder (MDD). Impaired HPA feedback may be due to the lower glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) levels in the forebrain. GR levels are transcriptionally controlled by multiple untranslated alternative first exons, each with its own promoter providing a mechanism for tissue-specific fine-tuning of GR levels. Recently epigenetic methylation of these GR promoters was shown to modulate hippocampal GR levels. Here we investigate in post-mortem brain tissues whether in MDD HPA axis hyperactivity may be due to epigenetic modulation of GR transcript variants.Levels of GR alpha, GR beta and GR-P transcripts were homogeneous throughout the limbic system, with GR alpha being the most abundant (83%), followed by GR-P (5-6%) while GR beta was barely detectable (0.02%). Among the alternative first exons, 1B and 1C were the most active, while 1E and 1J showed the lowest expression and transcript 1F expressed intermediate levels of about 1%.In MDD, total GR levels were unaltered, although GRa was decreased in the amygdala and cingulate gyrus ( p < 0.05); transcripts containing exons 1B, 1C and 1F were lower, and 1D and 1J were increased in some regions. NGFI-A, a transcription factor of exon 1F was down-regulated in the hippocampus of MDD patients; concomitantly exon 1F expression was reduced. Bisulphite sequencing of the alternative promoters showed low methylation levels in both MDD and control brains. Promoter 1F was uniformly unmethylated, suggesting that reduced 1F transcript levels are not linked to promoter methylation but to the observed dearth of NGFI-A.Previous studies showed high methylation levels in the 1F promoter, associated with childhood abuse. Provided our donors were not abused, our results suggest that the pathomechanism of MDD is similar but nevertheless distinct from that of abuse victims, explaining the clinical similarity of both conditions and that susceptibility to depression may be either predisposed by early trauma or developed independent of such a condition. However, this should be further confirmed in dedicated studies in larger cohorts. (C) 2009 Elsevier Ltd. All rights reserved.