Institute of Biomedical Research, Yunnan University, Kunming 650500, China.
Institute of Biomedical Research, Yunnan University, Kunming 650500, China; Southwest United Graduate School, Kunming 650500, China.
Cell Rep. 2024 Mar 26;43(3):113964. doi: 10.1016/j.celrep.2024.113964. Epub 2024 Mar 13.
Microglia are versatile regulators in brain development and disorders. Emerging evidence links microRNA (miRNA)-mediated regulation to microglial function; however, the exact underlying mechanism remains largely unknown. Here, we uncover the enrichment of miR-137, a neuropsychiatric-disorder-associated miRNA, in the microglial nucleus, and reveal its unexpected nuclear functions in maintaining the microglial global transcriptomic state, phagocytosis, and inflammatory response. Mechanistically, microglial Mir137 deletion increases chromatin accessibility, which contains binding motifs for the microglial master transcription factor Pu.1. Through biochemical and bioinformatics analyses, we propose that miR-137 modulates Pu.1-mediated gene expression by suppressing Pu.1 binding to chromatin. Importantly, we find that increased Pu.1 binding upregulates the target gene Jdp2 (Jun dimerization protein 2) and that knockdown of Jdp2 significantly suppresses the impaired phagocytosis and pro-inflammatory response in Mir137 knockout microglia. Collectively, our study provides evidence supporting the notion that nuclear miR-137 acts as a transcriptional modulator and that this microglia-specific function is essential for maintaining normal adult brain function.
小胶质细胞是大脑发育和疾病中的多功能调节者。新出现的证据将 miRNA（microRNA）介导的调节与小胶质细胞功能联系起来；然而，确切的潜在机制在很大程度上仍不清楚。在这里，我们发现与神经精神疾病相关的 miRNA-137 在小胶质细胞核中富集，并揭示了其在维持小胶质细胞全转录组状态、吞噬作用和炎症反应中的意想不到的核功能。在机制上，小胶质细胞 Mir137 缺失会增加染色质的可及性，其中包含小胶质细胞主转录因子 Pu.1 的结合基序。通过生化和生物信息学分析，我们提出 miR-137 通过抑制 Pu.1 与染色质的结合来调节 Pu.1 介导的基因表达。重要的是，我们发现 Pu.1 结合的增加上调了靶基因 Jdp2（Jun 二聚化蛋白 2），并且 Jdp2 的敲低显著抑制了 Mir137 敲除小胶质细胞中吞噬作用和促炎反应的受损。总之，我们的研究提供了证据支持核 miR-137 作为转录调节剂的观点，并且这种小胶质细胞特异性功能对于维持正常的成年大脑功能是必不可少的。
