Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene.
Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene.
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搜索锂和丙戊酸的常见靶标可以确定锂对大鼠瘦素受体基因的新表观遗传作用。
DOI：
10.1038/tp.2015.90
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发表时间：
2015-07-14
影响因子：
6.8
通讯作者：
Potash JB
中科院分区：
文献类型：
--
作者：
Lee RS;Pirooznia M;Guintivano J;Ly M;Ewald ER;Tamashiro KL;Gould TD;Moran TH;Potash JB
表观遗传学可能在情绪稳定剂作用中起重要作用。丙戊酸（VPA）是一种组蛋白去乙酰化酶抑制剂，锂（Li）可能具有下游表观遗传作用。为了鉴定通常受两种情绪稳定剂影响的基因，并评估可能参与其作用机制的潜在表观遗传机制，我们向Brown Norway大鼠给予Li（N=12）、VPA（N=12）和正常食物（N=12）30天。从海马提取基因组DNA和mRNA。我们使用mRNA进行基因表达分析的Affyphin微阵列芯片，和通常由Li和VPA调节的基因，我们验证表达水平使用定量实时PCR。为了鉴定表达变化的潜在机制，基因组DNA经亚硫酸氢盐处理用于关键CpG岛“海岸”和启动子区域的焦磷酸测序，并且从海马组织和海马衍生的细胞系制备染色质以评估组蛋白的修饰。对于大多数基因，我们发现几乎没有证据表明DNA甲基化会对药物产生反应。然而，我们检测到组蛋白H3甲基化和乙酰化的瘦素受体基因，Lepr，治疗后与两种药物。VPA介导的对组蛋白的作用已得到证实，而Li效应构成了该药物转录去抑制的新机制。这些数据支持了Li和VPA的几个共同的转录靶点，并提供了证据表明瘦素信号传导作为两种情绪稳定剂的表观遗传靶点。进一步的工作可能有助于澄清大脑中的瘦素信号传导是否在双相情感障碍中的Li和VPA的治疗作用中发挥作用。
Epigenetics may have an important role in mood stabilizer action. Valproic acid (VPA) is a histone deacetylase inhibitor, and lithium (Li) may have downstream epigenetic actions. To identify genes commonly affected by both mood stabilizers and to assess potential epigenetic mechanisms that may be involved in their mechanism of action, we administered Li (N=12), VPA (N=12), and normal chow (N=12) to Brown Norway rats for 30 days. Genomic DNA and mRNA were extracted from the hippocampus. We used the mRNA to perform gene expression analysis on Affymetrix microarray chips, and for genes commonly regulated by both Li and VPA, we validated expression levels using quantitative real-time PCR. To identify potential mechanisms underlying expression changes, genomic DNA was bisulfite treated for pyrosequencing of key CpG island ‘shores' and promoter regions, and chromatin was prepared from both hippocampal tissue and a hippocampal-derived cell line to assess modifications of histones. For most genes, we found little evidence of DNA methylation changes in response to the medications. However, we detected histone H3 methylation and acetylation in the leptin receptor gene, Lepr, following treatment with both drugs. VPA-mediated effects on histones are well established, whereas the Li effects constitute a novel mechanism of transcriptional derepression for this drug. These data support several shared transcriptional targets of Li and VPA, and provide evidence suggesting leptin signaling as an epigenetic target of two mood stabilizers. Additional work could help clarify whether leptin signaling in the brain has a role in the therapeutic action of Li and VPA in bipolar disorder.
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DOI：
10.1017/s1461145712000703
发表时间：
2013-05
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Guo M;Huang TY;Garza JC;Chua SC;Lu XY
通讯作者：
Lu XY
影响因子：
2.7
作者：
Colella, S;Shen, L;Krahe, R
通讯作者：
Krahe, R
DOI：
10.1073/pnas.96.15.8745
发表时间：
1999-07-20
影响因子：
11.1
作者：
Chalecka-Franaszek, E;Chuang, DM
通讯作者：
Chuang, DM
影响因子：
3.8
作者：
Bosetti, F;Seemann, R;Manickam, P
通讯作者：
Manickam, P
影响因子：
7.6
作者：
Gould, Todd D.;O'Donnell, Kelley C.;Manji, Husseini K.
通讯作者：
Manji, Husseini K.