Non-coding RNA yREX3 from human extracellular vesicles exerts macrophage-mediated cardioprotection via a novel gene-methylating mechanism.

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Publication Year:
2024
Authors:
Alessandra Ciullo, Liang Li, Chang Li, Kara Tsi, Colin Farrell, Matteo Pellegrini, Eduardo Marban, Ahmed G E Ibrahim
PubMed ID:
38865332
Funding Grants:
Public Summary:
Heart cells release tiny packages called extracellular vesicles that carry small RNA molecules. These RNAs can influence the immune system. The researchers looked closely at one small RNA called yREX3, which is common in these vesicles during heart injury. They found that yREX3 helps protect the heart after a lack of blood flow (like during a heart attack) by turning off a specific gene called Pick1 in immune cells called macrophages. It does this by adding chemical tags to the DNA, which stops Pick1 from working. When Pick1 is turned off, the immune cells become better at clearing damaged tissue, reducing heart damage. Giving these specially altered immune cells to rats with heart attacks helped their hearts heal better. This shows that yREX3 plays an important role in protecting the heart through a new way of controlling gene activity.
Scientific Abstract:
BACKGROUND AND AIMS: Extracellular vesicles (EVs) secreted by cardiosphere-derived cells exert immunomodulatory effects through the transmission of small non-coding RNAs. METHODS: The mechanism and role of yREX3, a small Y RNA abundant in EVs in myocardial injury, was investigated. RESULTS: yREX3 attenuates cardiac ischaemic injury by selective DNA methylation. Synthetic yREX3 encapsulated in lipid nanoparticles triggers broad transcriptomic changes in macrophages, localizes to the nucleus, and mediates epigenetic silencing of protein interacting with C kinase-1 (Pick1) through methylation of upstream CpG sites. Moreover, yREX3 interacts with polypyrimidine tract binding protein 3 (PTBP3) to methylate the Pick1 gene locus in a DNA methyltransferase-dependent manner. Suppression of Pick1 in macrophages potentiates Smad3 signalling and enhances efferocytosis, minimizing heart necrosis in rats with myocardial infarction. Adoptive transfer of Pick1-deficient macrophages recapitulates the cardioprotective effects of yREX3 in vivo. CONCLUSIONS: These findings highlight the role of a small Y RNA mined from EVs with a novel gene-methylating mechanism.