High activity of the stress promoter contributes to susceptibility to stress in the tree shrew.
High activity of the stress promoter contributes to susceptibility to stress in the tree shrew.
复制标题
应激启动子的高活性有助于树鼩对应激的敏感性
DOI：
10.1038/srep24905
复制
发表时间：
2016-04-29
影响因子：
4.6
通讯作者：
Zhou JN
中科院分区：
文献类型：
--
作者：
Fang H;Sun YJ;Lv YH;Ni RJ;Shu YM;Feng XY;Wang Y;Shan QH;Zu YN;Zhou JN
在当今快节奏的社会中，压力越来越多地出现在日常生活中，并参与许多精神疾病的发病机制。促肾上腺皮质激素释放激素（CRH）在调节应激反应中起着关键作用。树鼩对应激反应的敏感性使其成为研究应激反应的理想动物模型。然而，其高应力敏感性的机制仍然未知。本研究证实了皮质醇是树鼩体内的主要激素，并且在急性应激后显著升高。本研究表明，树鼩 CRH -下丘脑-垂体-肾上腺（HPA）轴的功能与人类基本相同，对应激反应性的影响不大。使用CRH转录调控分析，我们发现了一个特殊的活性糖皮质激素受体反应元件（aGRE）的网站内的树鼩 CRH启动子，继续招募共激活因子，包括SRC-1（类固醇受体共激活因子-1），以促进CRH转录基础或毛喉素/地塞米松治疗条件下。当使用CAS9/CRISPR将aGRE敲入人HeLa细胞中的CRH启动子时，基础CRH mRNA增加。aGRE在形成“应激启动子”方面发挥关键作用，该启动子有助于CRH的高表达和对应激的易感性。这些发现暗示了特定人群中应激相关疾病的新分子基础。
Stress is increasingly present in everyday life in our fast-paced society and involved in the pathogenesis of many psychiatric diseases. Corticotrophin-releasing-hormone (CRH) plays a pivotal role in regulating the stress responses. The tree shrews are highly vulnerable to stress which makes them the promising animal models for studying stress responses. However, the mechanisms underlying their high stress-susceptibility remained unknown. Here we confirmed that cortisol was the dominate corticosteroid in tree shrew and was significantly increased after acute stress. Our study showed that the function of tree shrew CRH - hypothalamic-pituitary-adrenal (HPA) axis was nearly identical to human that contributed little to their hyper-responsiveness to stress. Using CRH transcriptional regulation analysis we discovered a peculiar active glucocorticoid receptor response element (aGRE) site within the tree shrew CRH promoter, which continued to recruit co-activators including SRC-1 (steroid receptor co-activator-1) to promote CRH transcription under basal or forskolin/dexamethasone treatment conditions. Basal CRH mRNA increased when the aGRE was knocked into the CRH promoter in human HeLa cells using CAS9/CRISPR. The aGRE functioned critically to form the “Stress promoter” that contributed to the higher CRH expression and susceptibility to stress. These findings implicated novel molecular bases of the stress-related diseases in specific populations.