LncCMRR Plays an Important Role in Cardiac Differentiation by Regulating the Purb/Flk1 Axis
LncCMRR Plays an Important Role in Cardiac Differentiation by Regulating the Purb/Flk1 Axis
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LncCMRR 通过调节 Purb/Flk1 轴在心脏分化中发挥重要作用
DOI：
10.1093/stmcls/sxac077
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发表时间：
2022
期刊：
影响因子：
5.2
通讯作者：
Guiying Wang
中科院分区：
文献类型：
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作者：
Yiwei Yang;Xing Wang;Yu Tan;Yanxin Xu;Xudong Guo;Yukang Wu;Wuchan Wang;Ruiqi Jing;Fugui Zhu;Dan Ye;Qingquan Zhang;Chenqi Lu;Jiuhong Kang;Guiying Wang
长链非编码rna （long noncoding rna, lncRNAs）作为重要的表观遗传调控因子，在发育过程和多种疾病中发挥着重要作用。然而，lncrna在早期心脏发育中的调控机制仍然有限。在这项研究中，我们鉴定了心脏中胚层相关的lncRNA （LncCMRR）。LncCMRR基因敲除（KO）可降低小鼠胚胎干细胞（ES）胚胎体分化过程中心脏中胚层和心肌细胞的形成电位。机制分析表明，LncCMRR与转录抑制因子PURB相互作用，抑制其在Flk1启动子区域的结合潜力，从而在心脏中胚层形成过程中保护Flk1的转录。我们还对LncCMRR KO后的差异表达基因进行了基因本体术语和信号通路富集分析，发现LncCMRR与心肌收缩、扩张型心肌病、肥厚型心肌病存在显著相关性。LncCMRR KO后，Flk1在E7.75时的表达水平和E17.5时的心肌厚度均显著降低，LncCMRR-KO小鼠的存活率和心功能指数也较野生型组显著降低。这些发现表明，早期心脏发育缺陷导致LncCMRR-KO小鼠成年期心脏功能异常。总之，我们的研究结果阐明了LncCMRR在心脏中胚层形成中的主要功能和调控机制，并为lncrna介导的小鼠ES细胞分化调控网络提供了新的见解。
As crucial epigenetic regulators, long noncoding RNAs (lncRNAs) play critical functions in development processes and various diseases. However, the regulatory mechanism of lncRNAs in early heart development is still limited. In this study, we identified cardiac mesoderm-related lncRNA (LncCMRR). Knockout (KO) of LncCMRR decreased the formation potential of cardiac mesoderm and cardiomyocytes during embryoid body differentiation of mouse embryonic stem (ES) cells. Mechanistic analyses showed that LncCMRR functionally interacted with the transcription suppressor PURB and inhibited its binding potential at the promoter region of Flk1, which safeguarded the transcription of Flk1 during cardiac mesoderm formation. We also carried out gene ontology term and signaling pathway enrichment analyses for the differentially expressed genes after KO of LncCMRR, and found significant correlation of LncCMRR with cardiac muscle contraction, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Consistently, the expression level of Flk1 at E7.75 and the thickness of myocardium at E17.5 were significantly decreased after KO of LncCMRR, and the survival rate and heart function index of LncCMRR-KO mice were also significantly decreased as compared with the wild-type group. These findings indicated that the defects in early heart development led to functional abnormalities in adulthood heart of LncCMRR-KO mice. Conclusively, our findings elucidate the main function and regulatory mechanism of LncCMRR in cardiac mesoderm formation, and provide new insights into lncRNA-mediated regulatory network of mouse ES cell differentiation.