EMBL-Australia Collaborating Group, Department of Genome Sciences, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia.
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia.
Sci Rep. 2019 Feb 14;9(1):2048. doi: 10.1038/s41598-018-37037-0.
Circular RNAs (circRNAs) exhibit unique properties due to their covalently closed nature. Models of circRNAs synthesis and function are emerging but much remains undefined about this surprisingly prevalent class of RNA. Here, we identified exonic circRNAs from human and mouse RNA-sequencing datasets, documenting multiple new examples. Addressing function, we found that many circRNAs co-sediment with ribosomes, indicative of their translation potential. By contrast, circRNAs with potential to act as microRNA sponges were scarce, with some support for a collective sponge function by groups of circRNAs. Addressing circRNA biogenesis, we delineated several features commonly associated with circRNA occurrence. CircRNA-producing genes tend to be longer and to contain more exons than average. Back-splice acceptor exons are strongly enriched at ordinal position 2 within genes, and circRNAs typically have a short exon span with two exons being the most prevalent. The flanking introns either side of circRNA loci are exceptionally long. Of note also, single-exon circRNAs derive from unusually long exons while multi-exon circRNAs are mostly generated from exons of regular length. These findings independently validate and extend similar observations made in a number of prior studies. Furthermore, we analysed high-resolution RNA polymerase II occupancy data from two separate human cell lines to reveal distinctive transcription dynamics at circRNA-producing genes. Specifically, RNA polymerase II traverses the introns of these genes at above average speed concomitant with an accentuated slow-down at exons. Collectively, these features indicate how a perturbed balance between transcription and linear splicing creates important preconditions for circRNA production. We speculate that these preconditions need to be in place so that looping interactions between flanking introns can promote back-splicing to raise circRNA production to appreciable levels.
环形 RNA（circRNAs）因其共价闭合的性质而表现出独特的性质。circRNAs 的合成和功能模型正在出现，但关于这种令人惊讶的普遍 RNA 类，仍有许多尚未定义。在这里，我们从人类和小鼠 RNA 测序数据集鉴定了外显子 circRNAs，记录了多个新的例子。在功能方面，我们发现许多 circRNAs 与核糖体共沉淀，表明它们具有翻译潜力。相比之下，具有充当 microRNA 海绵潜力的 circRNAs 很少，一些支持由 circRNAs 组的集体海绵功能。在研究 circRNA 的生物发生时，我们描绘了几个与 circRNA 发生相关的常见特征。circRNA 产生基因通常比平均长度长，并且包含更多的外显子。反向剪接受体外显子在基因内的顺序位置 2 处强烈富集，circRNAs 通常具有短的外显子跨度，其中两个外显子最为常见。circRNA 基因座两侧的侧翼内含子特别长。同样值得注意的是，单外显子 circRNAs 源自异常长的外显子，而多外显子 circRNAs 主要由常规长度的外显子产生。这些发现独立地验证并扩展了之前许多研究中所做的类似观察。此外，我们分析了来自两个不同人类细胞系的高分辨率 RNA 聚合酶 II 占据数据，以揭示 circRNA 产生基因的独特转录动态。具体而言，RNA 聚合酶 II 以高于平均速度穿过这些基因的内含子，同时在exon 处减速明显。总的来说，这些特征表明转录和线性剪接之间的平衡失调如何为 circRNA 产生创造重要的前提条件。我们推测，这些前提条件需要到位，以便侧翼内含子之间的环化相互作用可以促进反向剪接，从而将 circRNA 的产生提高到可观的水平。
