HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation
HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation
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E3 连接酶 CBX4 泛素化 HDAC7 参与情境恐惧调节记忆形成
DOI：
10.1523/jneurosci.2773-16.2017
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发表时间：
2017-04-05
影响因子：
5.3
通讯作者：
Wang, Yue
中科院分区：
文献类型：
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作者：
Jing, Xu;Sui, Wen-Hai;Wang, Yue
组蛋白乙酰化是一种表观遗传修饰，在长时记忆的形成中起着重要作用。最近，组蛋白去乙酰化酶（HDAC）抑制剂被证明可以促进记忆的形成，这提出了一个有趣的可能性，他们可能会被用来挽救记忆缺陷。然而，还需要进一步的研究来阐明个体HDAC在记忆中的作用。在这项研究中，我们证明了HDAC 7，在背海马C57 BL 6 J小鼠，有一个迟来的和持续的下降后，上下文恐惧条件（CFC）的培训（4-24小时），这是参与长期CFC记忆的形成。我们还发现HDAC 7通过泛素依赖性降解而减少。CBX 4是参与该过程的HDAC 7 E3连接酶之一。Nur 77作为HDAC 7的靶基因之一，在CFC训练后6-24 h增加，并相应地调节CFC记忆的形成。最后，HDAC 7还参与了其他依赖于海马的记忆的形成，包括Morris水迷宫和物体定位测试。目前的研究结果有助于理解HDAC 7在调节海马依赖性记忆中的分子和细胞机制。目前的研究结果证明了组蛋白去乙酰化酶7（HDAC 7）对海马依赖性记忆的影响。此外，我们还通过泛素依赖性蛋白降解确定了背景恐惧条件反射（CFC）中HDAC 7降低的机制。我们还验证了CBX 4是HDAC 7 E3连接酶之一。最后，我们证明Nur 77作为HDAC 7的重要靶点之一，参与CFC记忆的形成。所有这些蛋白质，包括HDAC 7、CBX 4和Nur 77，都可能成为预防衰老和神经系统疾病中记忆缺陷的潜在治疗靶点。
Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4–24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6–24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory. SIGNIFICANCE STATEMENT The current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases.