Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter
Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter
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DOI：
10.1111/jnc.12034
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发表时间：
2012-12-01
影响因子：
4.7
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
--
作者：
Furukawa-Hibi, Yoko;Yun, Jaesuk;Yamada, Kiyofumi
神经元PAS结构域4（NPAS 4）是一种脑特异性螺旋环螺旋转录因子，近年来被证明可调节GABA能抑制性神经元的发育。我们以前报道过，Npas4 mRNA表达水平降低，在海马的小鼠暴露于社会隔离或约束压力，这是伴随着损害的记忆，情绪行为，和海马神经发生。因此，NPAS4表达的减少可能在应激诱导的脑功能障碍中起作用。本研究旨在探讨胁迫对Npas4基因转录的调控作用，重点研究糖皮质激素（GC）对Npas4基因转录的影响。皮质酮治疗减少Npas4在额叶皮层和海马的表达，而肾上腺切除术引起的表达增加。GC受体（GR）拮抗剂米非司酮可抑制应激诱导的Npas4表达减少。在Npas4转录起始位点上游约2000至约1000处发现推定的负性糖皮质激素反应元件（GRES）。Npas4启动子活性增加米非司酮或突变的负GRE序列。染色质免疫沉淀试验表明，束缚应激增加了GR的结合Npas4启动子区在海马。这些结果表明，Npas4的转录下调压力通过结合激动剂结合GR其启动子。
Neuronal PAS domain 4 (NPAS4), a brain-specific helixloophelix transcription factor, has recently been shown to regulate the development of GABAergic inhibitory neurons. We previously reported that Npas4 mRNA expression levels were reduced in the hippocampus of mice exposed to social isolation or restraint stress, which was accompanied by impairment of memory, emotional behavior, and hippocampal neurogenesis. Therefore, the reduction of NPAS4 expression may play a role in stress-induced brain dysfunction. In this study, to investigate the transcriptional regulation of Npas4 by stress, we focused on the effect of glucocorticoids (GCs) upon Npas4 transcription. Corticosterone treatment reduced Npas4 expression in the frontal cortex and hippocampus, whereas adrenalectomy caused an increase in expression. GC receptor (GR) antagonist, mifepristone, inhibited the stress-induced reduction of Npas4 expression. Putative negative glucocorticoid response elements (GREs) were found -2000 to -1000 upstream of the Npas4 transcription initiation site. Npas4 promoter activity was increased by mifepristone or by mutation of the negative GRE sequences. A chromatin immunoprecipitation assay revealed that restraint stress increased the binding of GR to Npas4 promoter region in the hippocampus. These results suggest that transcription of Npas4 is down-regulated by stress via the binding of agonist-bound GR to its promoter.