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Brown Fat-Specific RNA Labeling Reveals A Network of Inter-Organ Communication by Secreted microRNAs

ABSTRACT: Extracellular miRNAs are emerging as key regulators of organismal homeostasis. Here, using tissue-specific RNA labeling based on uracil phosphoribosyltransferase (UPRT)-mediated incorporation of 4-thiouracil (4TU) in male mice, we develop a roadmap of miRNA transfer from brown adipose tissue (BAT) to other tissues, where they can act to regulate energy metabolism. We demonstrate that BAT secretes miRNAs in both small extracellular vesicles (sEVs) and associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in liver, muscle, and hypothalamus. Disruption of DICER in BAT leads to a significant depletion of multiple miRNAs in both BAT and distal tissues, including 80-90% decreases in the most abundant miRNAs in muscle. Target analyses, in vitro modeling, and PAR-CLIP analysis in muscle in vivo confirm that these BAT-secreted miRNAs directly interact with target mRNAs and alter mitochondrial function in recipient tissues. These findings provide a framework for understanding the role of BAT-secreted miRNAs in inter-organ communication.

ORGANISM(S): Mus musculus

PROVIDER: GSE333522 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Many stem cell populations exist in a quiescent state in vivo, exiting quiescence and entering the cell cycle in response to specific stimuli. In the case of skeletal muscle, the muscle stem cells (MuSCs, or “satellite cells”) are quiescent under normal homeostatic conditions and undergo activation and cell cycle entry in response to muscle fiber damage. Quiescent MuSCs are also much more potent than their proliferating progeny in assays of stem cell transplantation. In recent years, it has become increasingly apparent that the quiescent state is both actively maintained and dynamically regulated. However, most of the analyses of quiescent MuSCs have come from cells that have been removed from their niche in vivo, purified by fluorescence activated cell sorting, and then assay ex vivo. Although such cells are still in the quiescent state under these conditions, there is no doubt that significant biochemical changes will occur during the isolation and purification process. Thus, we have sought to examine the true in vivo quiescent state by analyzing the transcriptome of MuSCs. To achieve that, we have used techniques to label actively transcribing RNA in vivo using nucleoside analogs. In mice in which the enzyme uracil phosphoribosyltransferase (UPRT) is expressed specifically in MuSCs, administration of 4-thiouracil (4TU), which is converted to thiouridine (TU) by UPRT, resulted in labelling of MuSC transcripts, and the transcriptome could be analyzed following pull-down of TU-tagged RNA. Varying the timing of 4TU administration revealed the dynamic regulation of different subsets of transcripts. Notably, labeling transcripts during the isolation procedure revealed very active transcription of specific subsets of genes. Nevertheless, the ex vivo transcriptome remained largely reflective of the in vivo transcriptome. Using the transcriptional inhibitor, α-amanitin, we were also able to show that there was little difference between the steady-state transcript levels of the most highly expressed genes when comparing the ex vivo transcriptome with the in vivo transcriptome. Together, these data provide a novel view of the molecular regulation of the quiescent state at the transcriptional level, demonstrate the utility of these tools for probing transcriptional dynamics in vivo, and provide an invaluable resource for understanding stem cell state transitions.

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Brown Fat-Specific RNA Labeling Reveals A Network of Inter-Organ Communication by Secreted microRNAs

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