DataSheet_1_CRHR1 mediates the transcriptional expression of pituitary hormones and their receptors under hypoxia.docx

Hypothalamus-pituitary-adrenal (HPA) axis plays critical roles in stress responses under challenging conditions such as hypoxia, via regulating gene expression and integrating activities of hypothalamus-pituitary-targets cells. However, the transcriptional regulatory mechanisms and signaling pathways of hypoxic stress in the pituitary remain to be defined. Here, we report that hypoxia induced dynamic changes in the transcription factors, hormones, and their receptors in the adult rat pituitary. Hypoxia-inducible factors (HIFs), oxidative phosphorylation, and cAMP signaling pathways were all differentially enriched in genes induced by hypoxic stress. In the pituitary gene network, hypoxia activated c-Fos and HIFs with specific pituitary transcription factors (Prop1), targeting the promoters of hormones and their receptors. HIF and its related signaling pathways can be a promising biomarker during acute or constant hypoxia. Hypoxia stimulated the transcription of marker genes for microglia, chemokines, and cytokine receptors of the inflammatory response. Corticotropin-releasing hormone receptor 1 (CRHR1) mediated the transcription of Pomc, Sstr2, and Hif2a, and regulated the function of HPA axis. Together with HIF, c-Fos initiated and modulated dynamic changes in the transcription of hormones and their receptors. The receptors were also implicated in the regulation of functions of target cells in the pituitary network under hypoxic stress. CRHR1 played an integrative role in the hypothalamus-pituitary-target axes. This study provides new evidence for CRHR1 involved changes of hormones, receptors, signaling molecules and pathways in the pituitary induced by hypoxia.

下丘脑-垂体-肾上腺（hypothalamus-pituitary-adrenal, HPA）轴在低氧等应激条件下，通过调控基因表达、整合下丘脑-垂体靶细胞的活性，在应激反应中发挥关键作用。然而，垂体中低氧应激的转录调控机制与信号通路仍有待阐明。本研究发现，低氧可诱导成年大鼠垂体中转录因子、激素及其受体发生动态变化。低氧诱导因子（hypoxia-inducible factors, HIFs）、氧化磷酸化及环磷酸腺苷（cyclic adenosine monophosphate, cAMP）信号通路在低氧应激诱导的基因中均呈现差异富集。在垂体基因网络中，低氧可激活c-Fos与HIFs，并通过特异性垂体转录因子Prop1靶向激素及其受体的启动子。HIF及其相关信号通路有望成为急性或持续性低氧应激中的潜在生物标志物。低氧可刺激垂体中小胶质细胞标记基因、炎症反应相关趋化因子及细胞因子受体的转录。促肾上腺皮质激素释放激素受体1（corticotropin-releasing hormone receptor 1, CRHR1）可介导Pomc、Sstr2及Hif2a的转录，并调控HPA轴的功能。与HIF协同，c-Fos可启动并调控激素及其受体的转录动态变化。这些受体还参与了低氧应激下垂体网络中靶细胞功能的调控。CRHR1在下丘脑-垂体-靶轴中发挥整合作用。本研究为CRHR1参与低氧诱导的垂体激素、受体、信号分子及通路的改变提供了新证据。