Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation.

影响 RNA 二级结构的 RNA 编辑改变可能导致人类疾病。因此，我们研究了衰竭人类心脏中的 RNA 编辑。转录组测序表明，腺苷到肌苷 (A-to-I) RNA 编辑负责心肌中 80% 的编辑事件。人类心脏衰竭的特点是 RNA 编辑减少。这主要归因于蛋白质编码基因内含子中的 Alu 元件。与非衰竭左心室相比，在衰竭左心室中，166 个 circRNA 上调，7 个 circRNA 下调。大多数上调的 circRNA 与宿主基因中 RNA 编辑的减少有关。ADAR2 与从 A 到 I 编辑的 RNA 区域结合，在衰竭的人类心脏中含量减少。在体外， ADAR2 的减少会增加 circRNA 水平，这表明 ADAR2 水平减少对人类衰竭心脏中 circRNA 的增加具有因果影响。为了获得机制见解，我们进一步鉴定了一种在心力衰竭中编辑高度减少的上调 circRNA AKAP13。ADAR2 减少了 AKAP13 mRNA 前体中双链结构的形成，从而降低了 Alu 元件的稳定性以及所得 circRNA 的环化。circAKAP13 的过度表达损害了人诱导多能干细胞来源的心肌细胞的肌小节规律性。这些数据表明 ADAR2 介导人类心脏中的 A 到 I RNA 编辑。A-to-I RNA 编辑抑制 Alu 元件 dsRNA 结构的形成，有利于经典线性 mRNA 剪接并抑制 circRNA 的形成。这些发现与 RNA 编辑减少和 circRNA 水平增加的疾病相关，并为人类特异性调控 circRNA 形成提供了见解。