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.

表观遗传学在青少年大脑成熟过程中基因表达的调节中发挥着至关重要的作用。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有助于细胞信号级联的激活并导致中枢突触损失。然而，神经炎症表观遗传调控导致青少年抑郁症的确切机制仍不清楚。在这项研究中，我们发现，重要的表观遗传调节因子 Polycomb Group 1 (PCGF1) 的表达在青少年重度抑郁症 (MDD) 患者的血浆中以及抑郁症小鼠模型中的青少年小鼠的小胶质细胞中均有所下降。 。我们证明 PCGF1 可在体内和体外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春期小鼠的抑郁样行为。从机制上讲，PCGF1通过上调MMP10启动子区域的RING1B/H2AK119ub和EZH2/H3K27me3来抑制MMP10的转录，特异性抑制小胶质细胞介导的神经炎症。这些结果为了解青少年抑郁症的发病机制提供了宝贵的见解，强调了组蛋白修饰、神经炎症和神经损伤之间的潜在联系。