Nuclear microRNA-mediated transcriptional control determines adult microglial homeostasis and brain function

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. [Display omitted] •miR-137 exhibits a distinct enrichment in the nucleus of microglia•Loss of miR-137 alters the chromatin accessibility and transcriptomic state of microglia•The miR-137-Pu.1 interaction inhibits Pu.1-mediated gene expression•Nuclear miR-137 acts as a transcriptional modulator to control adult microglial homeostasis Li et al. show that miR-137 is highly enriched in the nucleus of microglia and exhibits a non-canonical role as a transcriptional modulator to control gene expression. Nuclear miR-137 inhibits Pu.1-mediated transcriptional activity by interacting with Pu.1 and attenuating its DNA-binding affinity, thus maintaining adult microglial homeostasis and brain function.