EZH2 Methyltransferase Activity Controls Pten Expression and mTOR Signaling during Fear Memory Reconsolidation
EZH2 Methyltransferase Activity Controls Pten Expression and mTOR Signaling during Fear Memory Reconsolidation
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DOI：
10.1523/jneurosci.0538-18.2018
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发表时间：
2018-08-29
影响因子：
5.3
通讯作者：
Lubin, Farah D.
中科院分区：
文献类型：
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作者：
Jarome, Timothy J.;Perez, Gabriella A.;Lubin, Farah D.
记忆恢复诱导神经元中转录和翻译调节增加的短暂时期，称为再巩固，其由蛋白激酶B（AKT）-哺乳动物雷帕霉素靶蛋白（mTOR）途径调节。然而，目前尚不清楚在再巩固过程中AKT-mTOR通路的激活是如何调节的。在这里，我们发现，在雄性大鼠中，背景恐惧记忆的恢复短暂地增加了Zeste同源物2（EZH 2）的增强子水平沿着增加的组蛋白H3赖氨酸27三甲基化（H3 K27 me 3）水平，这与磷酸酶和张力蛋白同源物（PTEN）水平的降低有关，PTEN是海马中AKT-mTOR依赖性信号传导的有效抑制剂。进一步的实验发现增加的H3 K27 me 3水平和Pten启动子和编码区的DNA甲基化，表明Pten基因的转录沉默。Pten H3 K27 me 3水平在训练后或恢复远程（旧）恐惧记忆后没有变化，这表明Pten抑制的这种机制是特定于新记忆的重新巩固。在体内siRNA介导的Ezh 2在海马体中的敲低废除了恢复诱导的H3 K27 me 3增加，并防止了PTEN水平的降低。Ezh 2敲低减弱了修复后AKT和mTOR磷酸化的增加，这可以通过同时减少Pten来恢复，表明H3 K27 me 3通过抑制Pten来调节AKT-mTOR磷酸化。与这些结果相一致，在提取之前在CA 1区敲低Ezh 2会在以后的测试中损害记忆。总的来说，这些结果表明EZH 2介导的H3 K27 me 3在抑制Pten转录中起关键作用，Pten转录是AKT-mTOR激活和记忆再巩固所必需的。
Memory retrieval induces a transient period of increased transcriptional and translational regulation in neurons called reconsolidation, which is regulated by the protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway. However, it is currently unknown how activation of the AKT-mTOR pathway is regulated during the reconsolidation process. Here, we found that in male rats retrieval of a contextual fear memory transiently increased Enhancer of Zeste Homolog 2 (EZH2) levels along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, which correlated with decreased levels of phosphatase and tensin homolog (PTEN), a potent inhibitor of AKT-mTOR-dependent signaling in the hippocampus. Further experiments found increased H3K27me3 levels and DNA methylation across the Pten promoter and coding regions, indicating transcriptional silencing of the Pten gene. Pten H3K27me3 levels did not change following training or after the retrieval of a remote (old) fear memory, suggesting that this mechanism of Pten repression was specific to the reconsolidation of a new memory. In vivo siRNA-mediated knockdown of Ezh2 in the hippocampus abolished retrieval-induced increases in H3K27me3 and prevented decreases in PTEN levels. Ezh2 knockdown attenuated increases in the phosphorylation of AKT and mTOR following retrieval, which could be restored by simultaneously reducing Pten, suggesting that H3K27me3 regulates AKT-mTOR phosphorylation via repression of Pten. Consistent with these results, knockdown of Ezh2 in area CA1 before retrieval impaired memory on later tests. Collectively, these results suggest that EZH2-mediated H3K27me3 plays a critical role in the repression of Pten transcription necessary for AKT-mTOR activation and memory reconsolidation following retrieval.