miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification
miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification
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DOI：
10.1073/pnas.1608256113
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发表时间：
2016-08
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影响因子：
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通讯作者：
Xiaopeng Shen;B. Soibam;Ashley L. Benham;Xueping Xu;M. Chopra;Xiaoping Peng;Wei Yu;Wenjing Bao
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文献类型：
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作者：
Xiaopeng Shen;B. Soibam;Ashley L. Benham;Xueping Xu;M. Chopra;Xiaoping Peng;Wei Yu;Wenjing Bao
与心肌和骨骼肌中富集的microRNAs （miRNAs）相比，我们对早期心脏祖细胞中表达的miRNAs知之甚少。在这里，我们发现中胚层后1 （Mesp1）可激活大量可能促进心肌细胞形成的mirna。miR-322/-503簇在心脏祖细胞的Mesp1谱系中富集程度最高，在发育中的心管中特异性表达，并通过靶向rna结合因子、cug结合蛋白elav -样家族成员1 （Celf1）来驱动早性心肌细胞形成。这项研究填补了我们关于mirna在心脏早期作用的知识空白，并确定了以前未报道的促进心脏再生的候选分子。了解早期心脏命运决定的机制可能会导致更好的方法来促进心脏再生。我们使用中胚层后1 (Mesp1)-Cre/Rosa26-EYFP报告系统来鉴定早期心脏祖细胞中富集的microrna （mirna）。这些miRNA基因大多具有mesp1结合位点和活性组蛋白特征。在基于钙瞬态的筛选试验中，我们发现了可能促进心肌细胞程序的mirna。x染色体miRNA簇miR-322/-503在Mesp1谱系中最富集，在筛选试验中最有效。它在环状心脏中特别表达。异位miR-322/-503模拟内源性时间模式，特异性地驱动心肌细胞程序，同时抑制神经谱系，可能是通过靶向rna结合蛋白cug结合蛋白Elav-like家族成员1 （Celf1）。因此，谱系承诺细胞中的早期mirna可能通过交叉抑制其他谱系在细胞命运决定中发挥重要作用。本研究中发现的mirna，特别是miR-322/-503，是早期心脏命运的有效调节因子。
Significance Compared with microRNAs (miRNAs) enriched in cardiac and skeletal muscles, little is known about miRNAs expressed in early cardiac progenitors. Here, we show that mesoderm posterior 1 (Mesp1) transactivates a large number of miRNAs that may promote cardiomyocyte formation. The miR-322/-503 cluster has the highest enrichment in the Mesp1 lineage of cardiac progenitor cells, is specifically expressed in the developing heart tube, and drives precocious cardiomyocyte formation by targeting an RNA-binding factor, CUG-binding protein Elav-like family member 1 (Celf1). This study fills a gap in our knowledge about miRNAs acting early in the cardiac program and identifies previously unreported candidates in promoting cardiac regeneration. Understanding the mechanisms of early cardiac fate determination may lead to better approaches in promoting heart regeneration. We used a mesoderm posterior 1 (Mesp1)-Cre/Rosa26-EYFP reporter system to identify microRNAs (miRNAs) enriched in early cardiac progenitor cells. Most of these miRNA genes bear MESP1-binding sites and active histone signatures. In a calcium transient-based screening assay, we identified miRNAs that may promote the cardiomyocyte program. An X-chromosome miRNA cluster, miR-322/-503, is the most enriched in the Mesp1 lineage and is the most potent in the screening assay. It is specifically expressed in the looping heart. Ectopic miR-322/-503 mimicking the endogenous temporal patterns specifically drives a cardiomyocyte program while inhibiting neural lineages, likely by targeting the RNA-binding protein CUG-binding protein Elav-like family member 1 (Celf1). Thus, early miRNAs in lineage-committed cells may play powerful roles in cell-fate determination by cross-suppressing other lineages. miRNAs identified in this study, especially miR-322/-503, are potent regulators of early cardiac fate.