Characterization of QKI Gene Expression, Genetics, and Epigenetics in Suicide Victims with Major Depressive Disorder
Characterization of QKI Gene Expression, Genetics, and Epigenetics in Suicide Victims with Major Depressive Disorder
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DOI：
10.1016/j.biopsych.2009.05.010
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发表时间：
2009-11-01
影响因子：
10.6
通讯作者：
Turecki, Gustavo
中科院分区：
文献类型：
--
作者：
Klempan, Timothy A.;Ernst, Carl;Turecki, Gustavo
背景：许多研究表明在不同的精神疾病中髓鞘形成和神经胶质基因的表达存在缺陷。我们研究了QKI的脑表达和遗传/表观遗传调控，QKI是一种对细胞发育和髓鞘形成至关重要的少突胶质细胞特异性RNA结合蛋白。方法：基于微阵列的QKI在被诊断为重度抑郁症的自杀患者(n=16)和对照组(n=13)的皮质和皮质下脑区的表达。这些发现也通过实时(定量聚合酶链式反应[qPCR])方法进行评估，QKI蛋白水平通过免疫印迹进行评估。结果：在Affymetrix芯片上检测了QKI多个转录本的信使RNA(MRNA)水平，发现与对照组相比，自杀患者的11个皮质区域以及海马体和杏仁体中的信使RNA(MRNA)水平显著降低。定量聚合酶链式反应证实了基因芯片的发现，并证实了QKI蛋白在眶前叶皮质的表达降低。对一部分个体的启动子变异和甲基化状态的分析没有发现抑郁症自杀者和对照组之间在遗传或表观遗传水平上的差异。结论：抑郁症自杀者多种QKI mRNA亚型持续减少的观察支持越来越多的证据表明髓鞘相关缺陷在精神疾病的病因中所起的作用。QKI在这一过程中的特定作用是通过它的表达减少以及与参与少突胶质细胞决定的基因的已知相互作用来暗示的；然而，导致这些变化的QKI基因变异仍有待确定。
Background: A number of studies have suggested deficits in myelination and glial gene expression in different psychiatric disorders. We examined the brain expression and genetic/epigenetic regulation of QKI, an oligodendrocyte-specific RNA binding protein important for cell development and myelination.Methods: The microarray-based expression of QKI was evaluated in cortical and subcortical brain regions from suicide victims with a diagnosis of major depression (n = 16) and control subjects (n = 13). These findings were also assessed with a real-time (quantitative polymerase chain reaction [qPCR]) approach, with QKI protein levels evaluated through immunoblotting. Identification of a QKI promoter sequence was then used to examine genetic and epigenetic variation at the QKI locus.Results: The messenger RNA (mRNA) levels of multiple transcripts of QKI were evaluated on Affymetrix microarrays, revealing significant reductions in 11 cortical regions and the hippocampus and amygdala of suicide victims compared with control subjects. Microarray findings were confirmed by qPCR, and reduced expression of QKI protein was identified in orbitofrontal cortex. Analysis of promoter variation and methylation state in a subset of individuals did not identify differences at the genetic or epigenetic level between depressed suicide victims and control subjects.Conclusions: The observation of consistent reductions in multiple isoforms of QKI mRNA in depressed suicide victims supports the growing body of evidence for a role of myelination-related deficits in the etiology of psychiatric disorders. A specific role of QKI in this process is implied by its reduced expression and known interactions with genes involved in oligodendrocyte determination; however, QKI gene variation responsible for these changes remains to be identified.