人细胞外囊泡中的非编码 RNA yREX3 通过一种新型基因甲基化机制发挥巨噬细胞介导的心脏保护作用。

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

机构信息

Cedars-Sinai Medical Center, Smidt Heart Institute, 8700 Beverly Blvd, 1090 Davis Bldg, Los Angeles, CA 90048, USA.

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.

出版信息

Eur Heart J. 2024 Aug 3;45(29):2660-2673. doi: 10.1093/eurheartj/ehae357.

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.

背景与目的

心肌球来源细胞分泌的细胞外囊泡（EVs）通过传递小非编码 RNA 发挥免疫调节作用。

方法

研究了 EVs 中丰富的小 Y RNA yREX3 在心肌损伤中的作用机制。

结果

yREX3 通过选择性 DNA 甲基化减轻心脏缺血损伤。包封在脂质纳米颗粒中的合成 yREX3 触发巨噬细胞中广泛的转录组变化，定位于细胞核，并通过上游 CpG 位点的甲基化介导与蛋白激酶 C 相互作用的激酶 1（Pick1）的表观遗传沉默。此外，yREX3 与多嘧啶 tract 结合蛋白 3（PTBP3）相互作用以依赖于 DNA 甲基转移酶的方式甲基化 Pick1 基因座。巨噬细胞中 Pick1 的抑制增强了 Smad3 信号传导并增强了噬作用，最大限度地减少了心肌梗死大鼠的心脏坏死。Pick1 缺陷型巨噬细胞的过继转移在体内重现了 yREX3 的心脏保护作用。