Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures
Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures
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DOI：
10.1523/jneurosci.0589-04.2004
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发表时间：
2004-06-16
影响因子：
5.3
通讯作者：
Nestler, EJ
中科院分区：
文献类型：
--
作者：
Tsankova, NM;Kumar, A;Nestler, EJ
电惊厥(ECS)是治疗抑郁症最有效的方法之一，其作用机制可能与基因表达调控有关。基因启动子区域的染色质重塑越来越被认为是基因表达的关键控制点，因此可能部分地介导了ECS对基因活性的急性和慢性影响。在这里，我们分析了组蛋白的翻译后修饰是染色质重塑的主要形式，在急性或重复ECS后30分钟、2小时和24小时，在大鼠海马区的几个基因启动子上如何改变。我们用染色质免疫沉淀法测定了c-fos、BDNF和CREB基因启动子的组蛋白H3和H4乙酰化和磷酸乙酰化水平，这些基因的表达被ECS改变。我们发现，除了少数例外，在整个急性和慢性时间过程研究中，H4乙酰化水平与c-fos、BDNF和CREB的mRNA水平相关，而H3的乙酰化和磷酸乙酰化更有选择性地被检测到。我们的发现表明，本研究中观察到的c-fos转录的慢性下调可能是在H4乙酰化水平上实现的，而BDNF转录的慢性上调可能是通过控制H3乙酰化来维持的，选择性地在BDNFP3和P4启动子上实现。这些数据首次提供了染色质重塑参与ECS诱导的脑内基因表达调控的体内证据，并将有助于理解ECS治疗抑郁症的潜在机制。
The mechanism of action of electroconvulsive seizures (ECS), one of the most effective treatments of major depression, may involve the regulation of gene expression. Chromatin remodeling at gene promoter regions is increasingly recognized as a key control point of gene expression and may, therefore, partly mediate acute and chronic effects of ECS on gene activity. Here, we assayed how posttranslational modifications of histones, a major form of chromatin remodeling, are altered at several gene promoters in rat hippocampus at 30 min, 2 hr, and 24 hr after acute or repeated ECS. We performed chromatin immunoprecipitation assays to measure levels of histone H3 and H4 acetylation and phosphoacetylation at the promoters of the c-fos, BDNF, and CREB ( cAMP response element-binding protein) genes, the expression of which is altered by ECS. We found that, with few exceptions, levels of H4 acetylation correlated with mRNA levels for c-fos, BDNF, and CREB throughout the acute and chronic time course study, whereas acetylation and phosphoacetylation of H3 were detected more selectively. Our findings suggest that the chronic downregulation of c-fos transcription, observed in this study, may be achieved at the level of H4 acetylation, whereas chronic upregulation of BDNF transcription may be sustained via control of H3 acetylation, selectively at the BDNF P3 and P4 promoters. These data provide the first in vivo demonstration of the involvement of chromatin remodeling in ECS-induced regulation of gene expression in the brain and will help in understanding the mechanisms underlying the efficacy of ECS in the treatment of depression.