DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.
DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.
复制标题
DOI：
10.1093/cercor/bhaa337
复制
发表时间：
2020-11
期刊：
影响因子：
3.7
通讯作者：
Jing Wei;Jia Hua Cheng;Nicholas J. Waddell;Zi-Jun Wang;Xiaodong Pang;Qing Cao;Aiyi Liu;Javed M. Chitam
中科院分区：
文献类型：
--
作者：
Jing Wei;Jia Hua Cheng;Nicholas J. Waddell;Zi-Jun Wang;Xiaodong Pang;Qing Cao;Aiyi Liu;Javed M. Chitam
新的证据表明，表观遗传机制调节与压力相关的精神障碍中的异常基因转录。然而，DNA 甲基化及其催化酶 DNA 甲基转移酶 (DNMT) 在此过程中的作用仍有待阐明。在这里，我们发现，暴露于慢性（两周）不可预测压力的雄性大鼠在压力停止后，前额皮质（PFC）（压力的关键目标区域）中的 Dnmt3a 显着减少。用 DNMT 抑制剂治疗无应激对照大鼠，重现了慢性不可预测应激对 PFC 中 AMPAR 表达和功能下降的影响。相比之下，应激动物 PFC 中 Dnmt3a 的过度表达可防止谷氨酸能反应的丧失。此外，压力引起的行为异常，包括识别记忆受损、攻击性增强和运动过度，在压力动物的前额皮质中 Dnmt3a 表达可以部分减弱。最后，我们发现应激大鼠 PFC 中存在全基因组 DNA 甲基化变化和转录组变化，这两种变化在多个神经通路上富集，包括谷氨酸突触和微管相关蛋白激酶信号传导。因此，这些结果认识到 DNA 表观遗传修饰在应激引起的突触功能以及认知和情绪过程紊乱中的潜在作用。
Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.