小胶质细胞是大脑发育和疾病的多功能调节因子。新的证据将microRNA(miRNA)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然未知。这里,我们发现了miR-137的富集,这是一种神经精神疾病相关的miRNA,在小胶质细胞核中,并揭示了其在维持小胶质细胞整体转录组状态方面的意想不到的核功能,吞噬作用,和炎症反应。机械上,小胶质细胞Mir137缺失增加染色质可及性,其中包含小胶质主转录因子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,增加的Pu.1结合上调了靶基因Jdp2(Jun二聚化蛋白2),而敲除Jdp2显著抑制了Mir137敲除小胶质细胞受损的吞噬作用和促炎反应.总的来说,我们的研究提供了支持以下观点的证据:核miR-137充当转录调节因子,并且这种小胶质细胞特异性功能对于维持正常成人脑功能至关重要.
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.