Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens.
Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens.
复制标题
DOI：
10.1523/jneurosci.1357-12.2012
复制
发表时间：
2012-11-28
期刊：
影响因子：
--
通讯作者：
Nestler EJ
中科院分区：
文献类型：
--
作者：
Sun H;Maze I;Dietz DM;Scobie KN;Kennedy PJ;Damez-Werno D;Neve RL;Zachariou V;Shen L;Nestler EJ
组蛋白修饰酶的失调与许多精神疾病有关。 G9a (Ehmt2) 是一种组蛋白甲基转移酶，可催化组蛋白 H3 在赖氨酸 9 (H3K9me2) 处的常染色二甲基化，最近被认为与介导慢性可卡因给药反应的神经和行为可塑性有关。在这里，我们发现，慢性吗啡与可卡因一样，会降低小鼠伏隔核（NAc）（大脑关键奖励区域）中的 G9a 表达和 H3K9me2 的整体水平。相比之下，NAc 中其他组蛋白甲基转移酶或去甲基化酶或其他甲基化组蛋白标记的水平不受慢性吗啡的影响。通过病毒介导的基因转移和条件诱变，我们发现NAc中G9a的过度表达会对抗吗啡奖赏和运动敏化，并同时促进镇痛耐受和纳洛酮沉淀的戒断，而NAc中G9a的下调则增强运动敏化并延迟镇痛耐受的发展。我们通过对 H3K9me2 在不存在和存在慢性吗啡的情况下在 NAc 中的分布进行全面的 ChIP-seq 分析来确定 G9a 的下游靶标。这些数据提供了对慢性吗啡对 H3K9me2 表观基因组调控的新见解，并提出了吗啡诱导的成瘾样行为产生的基于染色质的新机制。
Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has recently been implicated in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, while down-regulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive ChIP-seq analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine, and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise.