Iowa State University, Biomedical Sciences, Ames, IA 50011, USA.
Nucleic Acids Res. 2019 Apr 8;47(6):2884-2905. doi: 10.1093/nar/gkz034.
Circular RNAs (circRNAs) perform diverse functions, including the regulation of transcription, translation, peptide synthesis, macromolecular sequestration and trafficking. Inverted Alu repeats capable of forming RNA:RNA duplexes that bring splice sites together for backsplicing are known to facilitate circRNA generation. However, higher limits of circRNAs produced by a single Alu-rich gene are currently not predictable due to limitations of amplification and analyses. Here, using a tailored approach, we report a surprising diversity of exon-containing circRNAs generated by the Alu-rich Survival Motor Neuron (SMN) genes that code for SMN, an essential multifunctional protein in humans. We show that expression of the vast repertoire of SMN circRNAs is universal. Several of the identified circRNAs harbor novel exons derived from both intronic and intergenic sequences. A comparison with mouse Smn circRNAs underscored a clear impact of primate-specific Alu elements on shaping the overall repertoire of human SMN circRNAs. We show the role of DHX9, an RNA helicase, in splicing regulation of several SMN exons that are preferentially incorporated into circRNAs. Our results suggest self- and cross-regulation of biogenesis of various SMN circRNAs. These findings bring a novel perspective towards a better understanding of SMN gene function.
环状 RNA（circRNAs）具有多种功能，包括转录、翻译、肽合成、大分子隔离和运输的调控。已知能够形成 RNA:RNA 双链体的反向 Alu 重复序列可将剪接位点聚集在一起进行反式剪接，从而促进 circRNA 的产生。然而，由于扩增和分析的限制，目前尚无法预测单个富含 Alu 的基因产生的 circRNA 的上限。在这里，我们使用一种定制的方法，报告了由富含 Alu 的生存运动神经元（SMN）基因产生的具有令人惊讶多样性的内含子 circRNAs，这些基因编码 SMN，这是人类中必不可少的多功能蛋白。我们表明，大量的 SMN circRNAs 表达是普遍存在的。鉴定出的一些 circRNAs 含有来自内含子和基因间序列的新型外显子。与小鼠 Smn circRNAs 的比较强调了灵长类动物特异性 Alu 元件对塑造人类 SMN circRNAs 总体谱的明显影响。我们展示了 RNA 解旋酶 DHX9 在几种 SMN 外显子的剪接调控中的作用，这些外显子优先被整合到 circRNAs 中。我们的结果表明，各种 SMN circRNAs 的生物发生存在自我和交叉调节。这些发现为更好地理解 SMN 基因功能提供了新的视角。
