circRNA Biogenesis Competes with Pre-mRNA Splicing
circRNA Biogenesis Competes with Pre-mRNA Splicing
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DOI：
10.1016/j.molcel.2014.08.019
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发表时间：
2014-10-02
期刊：
影响因子：
16
通讯作者：
Kadener, Sebastian
中科院分区：
文献类型：
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作者：
Ashwal-Fluss, Reut;Meyer, Markus;Kadener, Sebastian
环状RNA（CircRNA）是一类广泛表达的非编码RNA。然而，它们的生物起源和可能的功能知之甚少。在这里，通过研究我们在神经元组织中发现的circRNA，我们提供了证据，证明动物circRNA是共转录产生的，它们的产生速率主要由内含子序列决定。我们证明了环化和剪接相互竞争。这些机制是组织特异性的，在动物中是保守的。有趣的是，我们观察到剪接因子muscleblind（MBL/MBNL 1）的第二个外显子在苍蝇和人类中被环化。该circRNA（circMbl）及其侧翼内含子含有保守的肌盲结合位点，其被MBL强烈且特异性地结合。MBL水平的调节强烈地影响circMbl生物合成，并且该作用依赖于MBL结合位点。总之，我们的数据表明，circRNA可以通过与线性剪接竞争而在基因调控中发挥作用。此外，我们确定肌盲是参与circRNA生物合成的一个因素。
Circular RNAs (circRNAs) are widely expressed noncoding RNAs. However, their biogenesis and possible functions are poorly understood. Here, by studying circRNAs that we identified in neuronal tissues, we provide evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences. We demonstrate that circularization and splicing compete against each other. These mechanisms are tissue specific and conserved in animals. Interestingly, we observed that the second exon of the splicing factor muscleblind (MBL/MBNL1) is circularized in flies and humans. This circRNA (circMbl) and its flanking introns contain conserved muscleblind binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL binding sites. Together, our data suggest that circRNAs can function in gene regulation by competing with linear splicing. Furthermore, we identified muscleblind as a factor involved in circRNA biogenesis.