Li Naigang, Du Jingyi, Yang Ying, Zhao Tiantian, Wu Dong, Peng Fan, Wang Dongshuang, Kong Linghua, Zhou Wenjuan, Hao Aijun
Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders, Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Childhood Psychiatry Unit, Shandong Mental Health Center, Jinan, China.
Mol Psychiatry. 2025 Mar;30(3):914-926. doi: 10.1038/s41380-024-02714-2. Epub 2024 Aug 30.
Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.
表观遗传学在青少年大脑成熟过程中调节基因表达方面起着至关重要的作用。在患有抑郁症的青少年中，小胶质细胞介导的慢性神经炎症可能会导致细胞信号级联反应的激活，并导致中枢突触丧失。然而，导致青少年抑郁症的神经炎症表观遗传调控的确切机制仍不清楚。在本研究中，我们发现多梳蛋白组1（PCGF1），一种重要的表观遗传调节因子，在青少年重度抑郁症（MDD）患者的血浆中以及在抑郁症小鼠模型的青少年小鼠小胶质细胞中表达均降低。我们证明，PCGF1在体内和体外均可减轻小胶质细胞介导的神经炎症，减少神经元损伤并改善青少年小鼠的抑郁样行为。从机制上讲，PCGF1通过上调MMP10启动子区域中的RING1B/H2AK119ub和EZH2/H3K27me3来抑制MMP10的转录，从而特异性抑制小胶质细胞介导的神经炎症。这些结果为青少年抑郁症的发病机制提供了有价值的见解，突出了组蛋白修饰、神经炎症和神经损伤之间的潜在联系。小胶质细胞PCGF1调节青少年小鼠抑郁样行为的潜在机制。小胶质细胞PCGF1通过调节MMP10启动子区域中的RING1B/H2AK119ub和EZH2/H3K27me3来抑制NF-κB/MAPK途径的激活，从而减轻神经炎症并改善青少年小鼠的抑郁样行为。
