组蛋白甲基转移酶 G9a 在可卡因诱导的可塑性中的重要作用。
Essential role of the histone methyltransferase G9a in cocaine-induced plasticity.
机构信息
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
出版信息
Science. 2010 Jan 8;327(5962):213-6. doi: 10.1126/science.1179438.
Abstract
Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor DeltaFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
摘要
可卡因引起的基因表达改变导致神经元形态和行为的变化，可能是可卡因成瘾的基础。在小鼠中，我们确定了组蛋白 3 赖氨酸 9（H3K9）二甲基化和赖氨酸二甲基转移酶 G9a 在可卡因诱导的结构和行为可塑性中的重要作用。反复给予可卡因可降低伏隔核中 H3K9 二甲基化的总体水平。这种组蛋白甲基化的减少是通过该脑区中 G9a 的抑制介导的，而 G9a 的抑制受可卡因诱导的转录因子 DeltaFosB 的调节。通过条件性突变和病毒介导的基因转移，我们发现 G9a 的下调增加了伏隔核神经元的树突棘可塑性，并增强了对可卡因的偏好，从而确立了组蛋白甲基化在可卡因的长期作用中的关键作用。
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