Epigenetic Regulation of Transcriptional Repression by Drugs of Abuse

基因表达的改变有助于大脑奖励回路的适应 与药物滥用有关的持续行为。基因转录的表观遗传调控 组蛋白的翻译后修饰正在成为一种重要的机制，用于 环境因素，包括滥用药物，以控制基因表达。确定组蛋白 修改对滥用药物作出反应的因子，并了解染色质调节如何影响 行为对于了解药物成瘾的神经基础至关重要。 这一过程的一个有趣的候选者是甲基DNA结合转录抑制因子MeCP2 因为这种蛋白质在大脑发育和功能中起着重要作用。已知MeCP2可抑制 它的靶基因通过招募组蛋白脱乙酰酶和甲基转移酶来实现。有趣的是， 鉴于活性依赖和药物诱导的转录机制之间的保守性 调控，我们最近发现MeCP2以一种活性依赖的方式在 在一个动态调节MeCP2抑制其目标基因BDNF能力的位置上的神经元。我们 假设MeCP2是可卡因调节转录的关键介质，并且 抑制性组蛋白甲基化的调节有助于药物增敏的发展 行为。我们建议通过结合生物化学分析来检验这一假设 可卡因依赖调节MeCP2和组蛋白甲基化的实验操作 这些过程在药物滥用的小鼠模型中进行。我们的具体目标是：1)检查功能 滥用药物对MeCP2的调节；2)研究表观遗传转录的作用 可卡因调节基因表达的抑制机制；以及3)评估 基因转录对药物诱导的行为敏化的表观遗传机制。 这些研究将通过定义有助于 可卡因对神经基因表达和行为的影响。表观遗传学的鉴定 滥用药物调控基因表达的机制可能揭示新的靶点 治疗药物成瘾的方法。

Alterations in gene expression contribute to the adaptations of brain reward circuits that underlie persistent behaviors associated with drug abuse. Epigenetic regulation of transcription mediated by posttranslational modification of histone proteins is emerging as an important mechanism used by environmental factors, including drugs of abuse, to control gene expression. Identifying the histone modifying factors that respond to drugs of abuse and understanding how chromatin regulation affects behavior are crucial for making progress toward understanding the neural basis of drug addiction. One intriguing candidate for this process is the methyl-DNA binding transcriptional represser MeCP2 as this protein plays important roles in brain development and function. MeCP2 is known to repress its target genes by recruiting both histone deacetylase and methyltransferase enzymes. Interestingly, given the conservation between activity-dependent and drug-induced mechanisms of transcriptional regulation, we have recently found that MeCP2 is phosphorylated in an activity-dependent manner in neurons at a site that dynamically modulates the ability of MeCP2 to repress its target gene Bdnf. We hypothesize that MeCP2 is a key mediator of cocaine-regulated transcription, and that the regulation of repressive histone methylation contributes to the development of drug sensitization behaviors. We propose to test this hypothesis by combining biochemical analyses of cocaine-dependent regulation of MeCP2 and histone methylation with experimental manipulation of these processes in mouse models of drug abuse. Our specific aims are: 1) to examine the functional regulation of MeCP2 by drugs of abuse; 2) to investigate the contribution of epigenetic transcriptional repression mechanisms to cocaine-regulated gene expression; and 3) to evaluate the contribution of epigenetic mechanisms of gene transcription to drug-induced behavioral sensitization. These studies will fill a critical gap in knowledge by defining new mechanisms that contribute to the effects of cocaine on both neuronal gene expression and behavior. The identification of epigenetic mechanisms involved in regulation of gene expression by drugs of abuse may reveal new targets for therapies in treatment of drug addiction.