Long Non-coding RNA ECRAR Triggers Post-natal Myocardial Regeneration by Activating ERK1/2 Signaling

作者：Yanmei Chen, Xinzhong Li, Bing Li, He Wang, MengSha Li, Senlin Huang, Yili Sun, Guojun Chen, Xiaoyun Si, Chixiong Huang, Wangjun Liao, Yulin Liao, Jianping Bin · 发表于：Molecular Therapy · 年份：2018 · DOI：10.1016/j.ymthe.2018.10.021 · 被引用次数：93 · 研究领域：Cancer-related molecular mechanisms research、Congenital heart defects research、Cardiac Fibrosis and Remodeling

Reactivating post-natal myocardial regeneration potential may be a feasible strategy to regenerate the injured adult heart. Long non-coding RNAs (lncRNAs) have been implicated in regulating cellular differentiation, but whether they can elicit a regenerative response in the post-natal heart remains unknown. In this study, by characterizing the lncRNA transcriptome in human hearts during the fetal-to-adult transition, we found that 3,092 lncRNAs were differentially expressed, and we further identified a novel upregulated fetal lncRNA that we called endogenous cardiac regeneration-associated regulator (ECRAR), which promoted DNA synthesis, mitosis, and cytokinesis in post-natal day 7 and adult rat cardiomyocytes (CMs). Overexpression of ECRAR markedly stimulated myocardial regeneration and induced recovery of cardiac function after myocardial infarction (MI). Knockdown of ECRAR inhibited post-natal day 1 CM proliferation and prevented post-MI recovery. ECRAR was transcriptionally upregulated by E2F transcription factor 1 (E2F1). In addition, ECRAR directly bound to and promoted the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), resulting in downstream targets of cyclin D1 and cyclin E1 activation, which, in turn, activated E2F1. The E2F1-ECRAR-ERK1/2 signaling formed a positive feedback loop to drive cell cycle progression, and, therefore, it promoted CM proliferation. These findings indicated that our newly discovered ECRAR may be a valuable therap...