EZH2/miR-15a-5p/CXCL10 轴在抑郁样行为大鼠中的保护机制。

Protective mechanism of the EZH2/microRNA-15a-5p/CXCL10 axis in rats with depressive-like behaviors.

机构信息

Mental Health Center, West China Hospital, Sichuan University, Chengdu 610000, Sichuan, China; Mental Medicine College, The Medical University of Wenzhou, Wenzhou 325000 Zhejiang, China; Clinical Psychology Department, Nanchong Centre Hospital Affiliated to the Medical College of North Sichuan, Nanchong 637000, Sichuan, China.

Department of Psychiatry, the No. 1 Hospital Affiliated to The Medical University of Wenzhou, Wenzhou 325000 Zhejiang, China.

出版信息

J Chem Neuroanat. 2023 Oct;132:102283. doi: 10.1016/j.jchemneu.2023.102283. Epub 2023 May 4.

DOI:10.1016/j.jchemneu.2023.102283

PMID:37146769

Abstract

OBJECTIVE

Enhancer of zeste homolog 2 (EZH2), microRNA-15a-5p (miR-15a-5p), and chemokine C-X-C ligand 10 (CXCL10) have been studied in many diseases. However, the investigation of the EZH2/miR-15a-5p/CXCL10 axis in depression is not sufficient. Our study aimed to investigate the regulatory functions of the EZH2/miR-15a-5p/CXCL10 axis in rats with depressive-like behaviors.

METHODS

The rat model of depression-like behaviors was established by chronic unpredictable mild stress (CUMS), and EZH2, miR-15a-5p, and CXCL10 expression levels in rats with depression-like behaviors were detected. The silenced EZH2 or enhanced miR-15a-5p recombinant lentivirus was injected into the rats with depression-like behaviors to assess the changes in behavioral tests, hippocampal pathological structure, levels of inflammatory cytokines in the hippocampus, and hippocampal neuron apoptosis. The regulatory relationships among EZH2, miR-15a-5p, and CXCL10 were measured.

RESULTS

miR-15a-5p expression was reduced, and EZH2 and CXCL10 expression levels were elevated in rats with depressive-like behaviors. Downregulation of EZH2 or elevation of miR-15a-5p improved depressive behavior, and inhibited hippocampal inflammatory response and hippocampal neuron apoptosis. EZH2 promoted histone methylation at the promoter of miR-15a-5p, and miR-15a-5p bound to CXCL10 to inhibit its expression.

CONCLUSION

Our study summarizes that EZH2 promotes the hypermethylation of the miR-15a-5p promoter, thereby promoting CXCL10 expression. Upregulation of miR-15a-5p or inhibition of EZH2 can improve the symptoms in rats with depressive-like behaviors.

摘要

目的

EZH2（ Enhancer of zeste homolog 2 ）、miR-15a-5p（microRNA-15a-5p）和趋化因子 C-X-C 配体 10（CXCL10）在许多疾病中已得到研究。然而，EZH2/miR-15a-5p/CXCL10 轴在抑郁症中的研究尚不充分。本研究旨在探讨 EZH2/miR-15a-5p/CXCL10 轴在具有抑郁样行为的大鼠中的调控作用。

方法

通过慢性不可预测轻度应激（CUMS）建立具有抑郁样行为的大鼠模型，并检测具有抑郁样行为的大鼠中 EZH2、miR-15a-5p 和 CXCL10 的表达水平。将沉默 EZH2 或增强 miR-15a-5p 的重组慢病毒注入具有抑郁样行为的大鼠中，以评估行为测试、海马病理结构、海马炎症因子水平和海马神经元凋亡的变化。测量 EZH2、miR-15a-5p 和 CXCL10 之间的调控关系。

结果

具有抑郁样行为的大鼠中 miR-15a-5p 的表达降低，而 EZH2 和 CXCL10 的表达水平升高。下调 EZH2 或上调 miR-15a-5p 可改善抑郁行为，并抑制海马炎症反应和海马神经元凋亡。EZH2 促进 miR-15a-5p 启动子的组蛋白甲基化，而 miR-15a-5p 结合 CXCL10 抑制其表达。