2. Academic Validation
  3. Nuclear microRNA-mediated transcriptional control determines adult microglial homeostasis and brain function

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

  • Cell Rep. 2024 Mar 13;43(3):113964. doi: 10.1016/j.celrep.2024.113964.
Zhu Li 1,  Kexin Mao 2,  Lin Liu 1,  Shengyun Xu 1,  Min Zeng 1,  Yu Fu 1,  Jintao Huang 1,  Tingting Li 1,  Guoan Gao 1,  Zhao-Qian Teng 3,  Qinmiao Sun 4,  Dahua Chen 5,  Ying Cheng 6
Affiliations

Affiliations

  • 1 Institute of Biomedical Research, Yunnan University, Kunming 650500, China.
  • 2 Institute of Biomedical Research, Yunnan University, Kunming 650500, China; Southwest United Graduate School, Kunming 650500, China.
  • 3 Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 Institute of Biomedical Research, Yunnan University, Kunming 650500, China; Southwest United Graduate School, Kunming 650500, China. Electronic address: chendh@ynu.edu.cn.
  • 6 Institute of Biomedical Research, Yunnan University, Kunming 650500, China; Southwest United Graduate School, Kunming 650500, China. Electronic address: ycheng@ynu.edu.cn.
PMID: 38489263 DOI: 10.1016/j.celrep.2024.113964
Abstract

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.

Keywords

CP: Molecular biology; CP: Neuroscience; Jdp2; Pu.1; chromatin; miR-137; microglia; neurodevelopment; nuclear miRNA; transcription.

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