Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
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DOI：
10.3390/cells9071616
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发表时间：
2020-07-01
期刊：
影响因子：
6
通讯作者：
Dieterich, Christoph
中科院分区：
文献类型：
--
作者：
Jakobi, Tobias;Siede, Dominik;Dieterich, Christoph
几十年来，心血管疾病（CVD）一直是大多数发达国家的首要死亡原因。一些研究将 RNA 剪接以及最近的环状 RNA (circRNA) 与 CVD 联系起来。 CircRNA 源自线性转录本，并已被证明表现出组织特异性表达谱。在这里，我们对序列、结构、修饰和心脏 circRNA 相互作用进行了深入分析。我们使用人类诱导多能干细胞来源的心肌细胞 (hiPSC-CM)、人类健康和患病（缺血性心肌病、扩张型心肌病）心脏组织和人类脐静脉内皮细胞 (HUVEC) 来分析 circRNA。我们确定了所有样本中共享的 circRNA，以及模型特定的 circRNA 特征。基于这些 circRNA，我们在人、猪和小鼠心脏中鉴定了 63 个位置保守且表达的 circRNA。此外，我们发现circRNA的序列可能偏离基因组序列的序列，这是评估潜在功能的重要因素。额外数据的整合产生了 circRNA m(6)A 甲基化的证据，可能与翻译相关，并且 circRNA 与潜在的 Argonaute 2 结合位点重叠，表明与 RISC 复合体的潜在关联。此外，我们首次在心脏模型系统中描述了包含其初级转录物起始密码子（AUG circRNA）的circRNA子类，并观察到AUG circRNA的m（6）A甲基化富集。
For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression profiles. Here, we present an in-depth analysis of sequence, structure, modification, and cardiac circRNA interactions. We used human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), human healthy and diseased (ischemic cardiomyopathy, dilated cardiomyopathy) cardiac tissue, and human umbilical vein endothelial cells (HUVECs) to profile circRNAs. We identified shared circRNAs across all samples, as well as model-specific circRNA signatures. Based on these circRNAs, we identified 63 positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m(6)A-methylation of circRNAs, potentially linked to translation, as well as, circRNAs overlapping with potential Argonaute 2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m(6)A-methylation for AUG circRNAs.