The conserved long non-coding RNA CARMA regulates cardiomyocyte differentiation
The conserved long non-coding RNA CARMA regulates cardiomyocyte differentiation
复制标题
保守的长链非编码RNA CARMA调控心肌细胞分化
DOI：
10.1093/cvr/cvab281
复制
发表时间：
2021-09-06
影响因子：
10.8
通讯作者：
Pedrazzini, Thierry
中科院分区：
文献类型：
--
作者：
Kay, Maryam;Soltani, Bahram M.;Pedrazzini, Thierry
从多能干细胞中产生功能性心肌细胞需要严格控制分化过程。长链非编码RNA（lncRNA）在细胞发育过程中发挥重要的调控功能。在这项研究中，我们设计了一个综合的方法来确定在分化的人胚胎干细胞（ESCs）的心脏发生牵连的lncRNA。方法和结果我们鉴定了CARMA（心肌细胞成熟相关lncRNA），这是一种控制人ESC中心肌细胞分化和成熟的保守lncRNA。CARMA位于MIR-1-1HG附近，MIR-1- 1HG是两种心源性miRNA的宿主基因：MIR 1 -1和MIR-133 a2，并以反义方向转录。CARMA和miRNAs的表达呈负相关，CARMA敲除增加了MIR 1 -1和MIR 133 a2的表达。此外，CARMA具有MIR-133 a2结合位点，表明lncRNA也可能是miRNA作用的靶标。在CARMA下调后，MIR-133 a2靶蛋白编码基因协同下调。其中，我们发现了RBPJ，编码NOTCH通路效应子的基因。已经显示NOTCH控制中胚层和神经外胚层谱系之间的二元细胞命运决定，并且NOTCH抑制导致以神经外胚层衍生物为代价的增强的心肌细胞分化。有趣的是，两个lncRNA，linc 1230和linc 1335，这是已知的神经外胚层特化的阻遏物，被发现上调后，Notch 1沉默在胚胎干细胞。linc 1230或linc 1335的强制表达改善了ESC衍生的心肌细胞的产生。这两种lncRNA也被发现在ESC中的CARMA敲低后上调。总之，这些数据表明存在一个网络，涉及三个新鉴定的lncRNA，两个myomirs MIR 1 -1和MIR 133 a2和NOTCH信号通路，协调调节ESCs的心源性分化。
Aims Production of functional cardiomyocytes from pluripotent stem cells requires tight control of the differentiation process. Long non-coding RNAs (lncRNAs) exert critical regulatory functions in cell specification during development. In this study, we designed an integrated approach to identify lncRNAs implicated in cardiogenesis in differentiating human embryonic stem cells (ESCs). Methods and results We identified CARMA (CARdiomyocyte Maturation-Associated lncRNA), a conserved lncRNA controlling cardiomyocyte differentiation and maturation in human ESCs. CARMA is located adjacent to MIR-1-1HG, the host gene for two cardiogenic miRNAs: MIR1-1 and MIR-133a2, and transcribed in an antisense orientation. The expression of CARMA and the miRNAs are negatively correlated, and CARMA knockdown increases MIR1-1 and MIR-133a2 expression. In addition, CARMA possesses MIR-133a2 binding sites, suggesting the lncRNA could be also a target of miRNA action. Upon CARMA down-regulation, MIR-133a2 target protein-coding genes are coordinately down-regulated. Among those, we found RBPJ, the gene encoding the effector of the NOTCH pathway. NOTCH has been shown to control a binary cell fate decision between the mesoderm and the neuroectoderm lineages, and NOTCH inhibition leads to enhanced cardiomyocyte differentiation at the expense of neuroectodermal derivatives. Interestingly, two lncRNAs, linc1230 and linc1335, which are known repressors of neuroectodermal specification, were found up-regulated upon Notch1 silencing in ESCs. Forced expression of either linc1230 or linc1335 improved ESC-derived cardiomyocyte production. These two lncRNAs were also found up-regulated following CARMA knockdown in ESCs. Conclusions Altogether, these data suggest the existence of a network, implicating three newly identified lncRNAs, the two myomirs MIR1-1 and MIR-133a2 and the NOTCH signalling pathway, for the coordinated regulation of cardiogenic differentiation in ESCs.