Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes
Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes
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DOI：
10.1038/npp.2009.188
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发表时间：
2010-02-01
影响因子：
7.6
通讯作者：
Zschocke, Juergen
中科院分区：
文献类型：
--
作者：
Perisic, Tatjana;Zimmermann, Nicole;Zschocke, Juergen
大脑中异常的生化过程经常沿着细胞表观遗传特征的微妙变化，这可能支持精神疾病的致病进展。虽然最近的报道暗示某些抗抑郁药和情绪稳定剂能够调节表观遗传参数，但缺乏在相同条件下比较这些化合物作用的研究。在这项研究中，我们筛选了阿米替林（AMI），文拉法辛，西酞普兰，以及丙戊酸（VPA），卡马西平，拉莫三嗪的潜在行动的全球和局部表观遗传修饰在大鼠原代星形胶质细胞。在所有药物中，VPA暴露引起最强的全局染色质修饰，包括组蛋白H3/H4超乙酰化、2 MeH 3 K9低甲基化和DNA去甲基化，分别通过蛋白质印迹和发光甲基化分析测定。CpG去甲基化的发生独立于DNA甲基转移酶（DNMT）抑制。引人注目的是，AMI还诱导了轻微的胞嘧啶去甲基化，但不影响整体组蛋白乙酰化状态。局部，VPA诱导的染色质修饰反映在谷氨酸转运蛋白（GLT-1）启动子，如亚硫酸氢盐测序和乙酰化组蛋白H4染色质免疫沉淀分析所示。在VPA作用下，GLT-1启动子远端部分的独特CpG位点发生去甲基化，并富含乙酰化组蛋白H4。我们第一次证明这些变化与这种星形胶质细胞特异性基因的转录增强有关。相比之下，AMI未能刺激GLT-1转录和改变启动子甲基化水平。总之，VPA和AMI在全球范围内发挥染色质调节活性，使用不同的机制，在星形胶质细胞基因位点的分歧沉淀。Neuropsychopharmacology（2010）35，792-805; doi：10.1038/npp.2009.188; 2009年11月18日在线发表
Aberrant biochemical processes in the brain frequently go along with subtle shifts of the cellular epigenetic profile that might support the pathogenic progression of psychiatric disorders. Although recent reports have implied the ability of certain antidepressants and mood stabilizers to modulate epigenetic parameters, studies comparing the actions of these compounds under the same conditions are lacking. In this study, we screened amitriptyline (AMI), venlafaxine, citalopram, as well as valproic acid (VPA), carbamazepine, and lamotrigine for their potential actions on global and local epigenetic modifications in rat primary astrocytes. Among all drugs, VPA exposure evoked the strongest global chromatin modifications, including histone H3/H4 hyperacetylation, 2MeH3K9 hypomethylation, and DNA demethylation, as determined by western blot and luminometric methylation analysis, respectively. CpG demethylation occurred independently of DNA methyltransferase (DNMT) suppression. Strikingly, AMI also induced slight cytosine demethylation, paralleled by the reduction in DNMT enzymatic activity, without affecting the global histone acetylation status. Locally, VPA-induced chromatin modifications were reflected at the glutamate transporter (GLT-1) promoter as shown by bisulfite sequencing and acetylated histone H4 chromatin immunoprecipitation analysis. Distinct CpG sites in the distal part of the GLT-1 promoter were demethylated and enriched in acetylated histone H4 in response to VPA. For the first time, we could show that these changes were associated with an enhanced transcription of this astrocyte-specific gene. In contrast, AMI failed to stimulate GLT-1 transcription and to alter promoter methylation levels. In conclusion, VPA and AMI globally exerted chromatin-modulating activities using different mechanisms that divergently precipitated at an astroglial gene locus. Neuropsychopharmacology (2010) 35, 792-805; doi:10.1038/npp.2009.188; published online 18 November 2009