Urquhart Kyle R, Zhao Yinghong, Baker Jessica A, Lu Ye, Yan Lei, Cook Melloni N, Jones Byron C, Hamre Kristin M, Lu Lu
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Neurogenetics. 2016 Apr;17(2):91-105. doi: 10.1007/s10048-015-0470-0. Epub 2016 Jan 18.
Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds. The hippocampus is an important mediator of these responses, and thus, was examined in the BXD family of mice in this study. We conducted bioinformatic analyses to dissect genetic factors modulating Hspa8 expression, identify downstream targets of Hspa8, and examined its role. Hspa8 is trans-regulated by a gene or genes on chromosome 14 and is part of a molecular network that regulates stress- and ethanol-related behaviors. To determine additional components of this network, we identified direct or indirect targets of Hspa8 and show that these genes, as predicted, participate in processes such as protein folding and organic substance metabolic processes. Two phenotypes that map to the Hspa8 locus are anxiety-related and numerous other anxiety- and/or ethanol-related behaviors significantly correlate with Hspa8 expression. To more directly assay this relationship, we examined differences in gene expression following exposure to stress or alcohol and showed treatment-related differential expression of Hspa8 and a subset of the members of its network. Our findings suggest that Hspa8 plays a vital role in genetic differences in responses to stress and ethanol and their interactions.
遗传差异介导了个体在对应激和乙醇的易感性及反应方面的差异，尽管控制这些反应的具体分子途径尚未完全明确。热休克蛋白α8（Hspa8）是一种分子伴侣，属于热休克蛋白家族，在应激反应中发挥着不可或缺的作用，并且被认为是一个乙醇反应基因。因此，我们评估了它在不同遗传背景下介导对应激和乙醇反应中的作用。海马体是这些反应的重要调节者，因此，在本研究中我们对BXD小鼠家族的海马体进行了检测。我们进行了生物信息学分析，以剖析调节Hspa8表达的遗传因素，确定Hspa8的下游靶点，并研究其作用。Hspa8受14号染色体上一个或多个基因的反式调控，并且是调节应激和乙醇相关行为的分子网络的一部分。为了确定该网络的其他组成部分，我们确定了Hspa8的直接或间接靶点，并表明这些基因正如所预测的那样，参与了诸如蛋白质折叠和有机物质代谢过程等。两种定位于Hspa8基因座的表型与焦虑相关，并且许多其他与焦虑和/或乙醇相关的行为与Hspa8表达显著相关。为了更直接地分析这种关系，我们检测了暴露于应激或酒精后基因表达的差异，并显示了与处理相关的Hspa8及其网络中一部分成员的差异表达。我们的研究结果表明，Hspa8在对应激和乙醇反应的遗传差异及其相互作用中起着至关重要的作用。
