Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
Elife. 2021 Jan 21;10:e63088. doi: 10.7554/eLife.63088.
Circular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs; however, the principles of biogenesis are currently not fully understood. Here, we identify two factors, splicing factor proline/glutamine rich (SFPQ) and non-POU domain-containing octamer-binding protein (NONO), to be enriched around circRNA loci. We observe a subclass of circRNAs, coined DALI circRNAs, with distal inverted elements and long flanking introns to be highly deregulated upon SFPQ knockdown. Moreover, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing, premature transcription termination, and polyadenylation, particularly prevalent for long introns. Aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we identify missplicing in the immediate upstream region to be a conserved driver of circRNA biogenesis. Collectively, our data show that SFPQ plays an important role in maintaining intron integrity by ensuring accurate splicing of long introns, and disclose novel features governing -independent circRNA production.
环状 RNA（circRNAs）是一类丰富且保守的非编码 RNA 分子；然而，其生物发生的原理目前还不完全清楚。在这里，我们鉴定了两个因子，剪接因子脯氨酸/谷氨酰胺丰富（SFPQ）和非 POU 域结合八聚体结合蛋白（NONO），它们在 circRNA 基因座周围富集。我们观察到一类称为 DALI circRNAs 的 circRNAs，它们具有远端反向元件和长侧翼内含子，在 SFPQ 敲低时高度失调。此外，SFPQ 耗竭导致内含子滞留增加，同时诱导隐性剪接、转录提前终止和多聚腺苷酸化，尤其是长内含子。circRNA 产生外显子上下游区域的异常剪接对于形成环状 RNA 组至关重要，特别是我们发现 immediate upstream region 的错误剪接是环状 RNA 生物发生的一个保守驱动因素。总的来说，我们的数据表明，SFPQ 通过确保长内含子的准确剪接，在维持内含子完整性方面发挥重要作用，并揭示了独立于剪接的环状 RNA 产生的新特征。
