Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Nature. 2013 Mar 21;495(7441):333-8. doi: 10.1038/nature11928. Epub 2013 Feb 27.
Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
环状 RNA（circRNAs）是一类具有未知功能的神秘 RNA 分子。为了系统地探索 circRNAs，我们对人类、小鼠和线虫的 RNA 进行了测序和计算分析。我们检测到了数千种表达良好、稳定的 circRNAs，它们通常表现出组织/发育阶段特异性表达。序列分析表明 circRNAs 具有重要的调控功能。我们发现，一个与小脑退化相关蛋白 1 转录物（CDR1as）反义的人类 circRNA 被 microRNA（miRNA）效应复合物紧密结合，并含有 63 个保守的结合位点，用于结合古老的 miRNA miR-7。进一步的分析表明，CDR1as 在神经元组织中作为 miR-7 的结合物发挥作用。人类 CDR1as 在斑马鱼中的表达会损害中脑发育，这与敲低 miR-7 的效果相似，这表明 CDR1as 是一种 miRNA 拮抗剂，其 miRNA 结合能力比任何其他已知转录本都要高出十倍。总的来说，我们的数据提供了证据表明 circRNAs 构成了一大类转录后调控因子。许多 circRNAs 通过外显子的头尾拼接形成，这表明编码序列具有以前未被认识到的调控潜力。
