Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.,Nature Communications

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Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-020-14331-y
Marco D Carpenter _{1,

2,

3} , Qiwen Hu _{1,

2,

3} , Allison M Bond _{3,

4} , Sonia I Lombroso _{1,

2,

3} , Kyle S Czarnecki _{1,

2,

3} , Carissa J Lim ₁ , Hongjun Song _{3,

4} , Mathieu E Wimmer ₅ , R Christopher Pierce ₆ , Elizabeth A Heller _{1,

2,

3}

Affiliation

Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrated the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.

中文翻译：

Nr4a1 通过稳态靶基因的表观遗传调节来抑制可卡因诱导的行为。

内源性稳态机制可以在可卡因诱导的神经适应后恢复正常的神经元功能。这种机制可用于开发可卡因成瘾的新疗法，但尚未确定分子靶点。在这里，我们分析了早期和晚期可卡因戒断期间的小鼠基因表达，以确定神经稳态的假定调节因子。可卡因激活转录因子 Nr4a1 及其靶基因 Cartpt（参与多巴胺代谢的关键分子）。戒断后期 Cartpt 的持续激活伴随着抑制性组蛋白修饰 H3K27me3 的耗尽以及激活标记 H3K27ac 和 H3K4me3 的富集。利用 CRISPR 介导的 Nr4a1 激活和小分子 Nr4a1 激活，我们证明了 Nr4a1 在 Cartpt 持续激活和减弱可卡因诱发行为中的直接因果作用。我们的研究结果提供了证据，表明针对戒断诱导的稳态基因表达是可卡因成瘾的潜在治疗靶点。

更新日期：2020-01-24

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