Reduction of lamin B receptor levels by miR-340-5p disrupts chromatin, promotes cell senescence and enhances senolysis
Reduction of lamin B receptor levels by miR-340-5p disrupts chromatin, promotes cell senescence and enhances senolysis
复制标题
DOI：
10.1093/nar/gkab538
复制
发表时间：
2021-06-28
影响因子：
14.9
通讯作者：
Gorospe, Myriam
中科院分区：
文献类型：
--
作者：
Herman, Allison B.;Anerillas, Carlos;Gorospe, Myriam
受microRNAs(MiRNAs)影响的主要应激反应是衰老，这是一种由亚致死性细胞损伤引发的无限期生长停滞状态。在这里，通过生物信息学分析和实验验证，我们确定miR-340-5p是一个新的引起细胞衰老的miRNA。MiR-340-5p在不同的衰老模型中高度表达，而miR-340-5p在增殖细胞中的过度表达使其衰老。在靶mRNAs中，miR-340-5p显著降低LBR基因的表达水平，编码LBR。通过在叶片相关区域异位过表达miR-340-5P来降低异染色质的表达，促进具有衰老特征的DNA重复元件的表达，从而丢失LBR。重要的是，miR-340-5p的过表达增强了细胞对衰老化合物的敏感性，而miR-340-5p的抗凝作用减少了衰老细胞标记物，并产生了对衰老诱导的细胞死亡的抵抗。我们认为miR-340-5P可以用于去除衰老细胞，以恢复组织动态平衡，减轻衰老细胞在人类衰老病理中的损害。
A major stress response influenced by microRNAs (miRNAs) is senescence, a state of indefinite growth arrest triggered by sublethal cell damage. Here, through bioinformatic analysis and experimental validation, we identified miR-340-5p as a novel miRNA that foments cellular senescence. miR-340-5p was highly abundant in diverse senescence models, and miR-340-5p overexpression in proliferating cells rendered them senescent. Among the target mRNAs, miR-340-5p prominently reduced the levels of LBR mRNA, encoding lamin B receptor (LBR). Loss of LBR by ectopic overexpression of miR-340-5p derepressed heterochromatin in lamina-associated domains, promoting the expression of DNA repetitive elements characteristic of senescence. Importantly, overexpressing miR-340-5p enhanced cellular sensitivity to senolytic compounds, while antagonization of miR-340-5p reduced senescent cell markers and engendered resistance to senolytic-induced cell death. We propose that miR-340-5p can be exploited for removing senescent cells to restore tissue homeostasis and mitigate damage by senescent cells in pathologies of human aging.