title: High activity of the stress promoter contributes to susceptibility to stress in the tree shrew.
abstract: 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.
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Yun-Jun
authors.initials: YJ
authors.lastname: Sun
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Lv
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Rong-Jun
authors.initials: RJ
authors.lastname: Ni
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Yu-Mian
authors.initials: YM
authors.lastname: Shu
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Xiu-Yu
authors.initials: XY
authors.lastname: Feng
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Qing-Hong
authors.initials: QH
authors.lastname: Shan
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Zu
authors.affiliation: CAS Key Laboratory of Brain Function and Disease, School of Life Science, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, Anhui, China.
authors.forename: Jiang-Ning
authors.initials: JN
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D006367:HeLa Cells; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D013312:Stress, Physiological; D014158:Transcription, Genetic; D014418:Tupaiidae / Q000502:physiology*
chemical_list: D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone