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

Abstract

ObjectiveEnhancer 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. MethodsThe 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. ResultsmiR-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. ConclusionOur 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.