Genome-Wide Analysis of Glucocorticoid-Responsive Transcripts in the Hypothalamic Paraventricular Region of Male Rats
Genome-Wide Analysis of Glucocorticoid-Responsive Transcripts in the Hypothalamic Paraventricular Region of Male Rats
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DOI：
10.1210/en.2018-00535
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发表时间：
2019-01-01
期刊：
影响因子：
4.8
通讯作者：
Aguilera, Greti
中科院分区：
文献类型：
--
作者：
Itoi, Keiichi;Motoike, Ikuko;Aguilera, Greti
糖皮质激素（GC）是压力适应所必需的，作用于中枢和外周。促肾上腺皮质激素释放因子（CRF）是肾上腺皮质激素合成的主要调节因子，产生于下丘脑室旁核（PVH），该核含有多种神经内分泌和前自主神经元。GC可能参与PVH中的多种调节机制，但GC的靶基因除了CRF基因（Crh）之外在很大程度上未被探索，CRF基因是GC负反馈的一个众所周知的靶基因。使用全基因组RNA测序分析，我们确定了响应于高剂量皮质酮（Cort）暴露12天（12天高Cort），皮质激素剥夺7天（7天ADX）或急性Cort给药的转录物。其中，典型的GC靶基因显著上调12天的高Cort。Crh上调或下调最显着的无论是7天的ADX或12天的高Cort，强调公认的反馈作用，GC对下丘脑-垂体-肾上腺（HPA）轴。加压素和爱帕琳受体基因表达的伴随变化可能有助于HPA抑制。与GC的多效性细胞作用一致，7天ADX下调了广泛功能谱的许多基因。急性Cort注射和12天高Cort之间的转录组反应特征显著不同。值得注意的是，6个立即早期基因上调Cort注射后1小时，这是证实了定量逆转录PCR和半定量原位杂交。本研究为进一步研究PVH中GC依赖性基因表达和阻遏的调控机制提供了数据。
Glucocorticoids (GCs) are essential for stress adaptation, acting centrally and in the periphery. Corticotropin-releasing factor (CRF), a major regulator of adrenal GC synthesis, is produced in the paraventricular nucleus of the hypothalamus (PVH), which contains multiple neuroendocrine and preautonomic neurons. GCs may be involved in diverse regulatory mechanisms in the PVH, but the target genes of GCs are largely unexplored except for the CRF gene (Crh), a well-known target for GC negative feedback. Using a genome-wide RNA-sequencing analysis, we identified transcripts that changed in response to either high-dose corticosterone (Cort) exposure for 12 days (12-day high Cort), corticoid deprivation for 7 days (7-day ADX), or acute Cort administration. Among others, canonical GC target genes were upregulated prominently by 12-day high Cort. Crh was upregulated or downregulated most prominently by either 7-day ADX or 12-day high Cort, emphasizing the recognized feedback effects of GC on the hypothalamic-pituitary-adrenal (HPA) axis. Concomitant changes in vasopressin and apelin receptor gene expression are likely to contribute to HPA repression. In keeping with the pleotropic cellular actions of GCs, 7-day ADX downregulated numerous genes of a broad functional spectrum. The transcriptome response signature differed markedly between acute Cort injection and 12-day high Cort. Remarkably, six immediate early genes were upregulated 1 hour after Cort injection, which was confirmed by quantitative reverse transcription PCR and semiquantitative in situ hybridization. This study may provide a useful database for studying the regulatory mechanisms of GC-dependent gene expression and repression in the PVH.