Single immobilization stress differentially alters the expression profile of transcripts of the brain-derived neurotrophic factor (BDNF) gene and histone acetylation at its promoters in the rat hippocampus
Single immobilization stress differentially alters the expression profile of transcripts of the brain-derived neurotrophic factor (BDNF) gene and histone acetylation at its promoters in the rat hippocampus
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DOI：
10.1017/s1461145708008997
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发表时间：
2009-02-01
影响因子：
4.8
通讯作者：
Yamawaki, Shigeto
中科院分区：
文献类型：
--
作者：
Fuchikami, Manabu;Morinobu, Shigeru;Yamawaki, Shigeto
海马区脑源性神经营养因子(BDNF)水平降低与抑郁症的病理生理机制有关，尽管其机制尚不清楚。表观遗传学研究表明，BDNF基因外显子启动子的DNA甲基化和组蛋白修饰是BDNF转录调控的关键因素。组蛋白乙酰化通过染色质重塑调节基因转录。采用实时定量聚合酶链式反应(RT-PCR)检测单次束缚应激(SIS)后2 h和24 h大鼠海马区各外显子总BDNF mRNA表达水平，染色质免疫沉淀结合实时荧光定量聚合酶链式反应(Real-time PCR)检测大鼠海马区BDNF基因启动子乙酰化组蛋白表达水平，ELISA法检测大鼠海马区BDNF蛋白表达水平。SIS后4h，BDNF总mRNA水平显著降低，外显子I、IVmRNA水平显著降低，BDNF蛋白水平显著降低。外显子1、TV和VI启动子的乙酰化组蛋白H3水平显著降低，而H4水平无明显变化。相反，SIS后24 h，乙酰化组蛋白和BDNFmRNA和蛋白水平均未见明显变化。本研究证实了组蛋白乙酰化参与了SIS对BDNF转录的调控，以及SIS后组蛋白乙酰化的可塑性变化。这些发现表明，应激通过表观遗传调控影响BDNF基因转录，糖皮质激素可能参与了这一调控。
Decreased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus are implicated in the pathophysiology of major depression, although the mechanism has yet to be characterized. Epigenetic studies revealed that DNA methylation and histone modifications at the promoter of exons of the BDNF gene are the pivotal factors in the regulation of BDNF transcription. Histone acetylation regulates gene transcription through chromatin remodelling. We examined the influence of a single immobilization stress (SIS) at 2 h and 24 h afterwards on the levels of total BDNF mRNA with each exon mRNA by quantitative real-time PCR, acetylated histone at the promoters of the BDNF gene by chromatin immunoprecipitation followed by real-time PCR, and BDNF protein by ELISA in the rat hippocampus. SIS significantly decreased the levels of total BDNF mRNA with significantly reduced levels of exons I and IV mRNA followed by a significant reduction in BDNF protein 4 h after SIS. Significant decreases in the levels of acetylated histone H3, but not H4, were found at the promoters of exons 1, TV, and VI. In contrast, no marked changes in the levels of either acetylated histone or BDNF mRNA and protein were found 24 h after SIS. This study demonstrated the involvement of histone acetylation in the regulation of BDNF transcription by SIS, and the plastic change in histone acetylation after SIS. These findings suggest that stress affects BDNF gene transcription via epigenetic regulation, and glucocorticoid may be involved in this regulation.