circRNA biogenesis competes with pre-mRNA splicing
Open accessAbstract
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.
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Transcription speed directly correlates with the circularization efficiency of circRNAs.
“Moreover, the use of slow and fast RNA Pol II mutants has shown that transcription speed directly correlates with the circularization efficiency of circRNAs (Ashwal‐Fluss et al, 2014; Zhang et al, 2016).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Ashwal‐Fluss et al, 2014
CircMBL contains conserved MBL/MBNL1 RNA binding sites derived from the second exon of the MBL mRNA; specific binding of circMBL to MBL mRNA regulates gene expression by inhibiting linear splicing of the MBL mRNA.
“Circular MBL (circMBL) contains conserved muscleblind (MBL/MBNL1) RNA binding sites, which are derived from the second exon of the MBL mRNA.The specific binding of circMBL to MBL mRNA regulates gene expression by inhibiting the linear splicing of the MBL mRNA [65].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [65]
Processing of linear mRNAs competes with the processing of circRNAs, resulting in a negative correlation between the splicing efficiency of certain genes and the generation of circRNAs.
“Processing of linear mRNAs competes with the processing of circRNAs, resulting in a negative correlation between the splicing efficiency of certain genes and the generation of circRNAs [65].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [65]
More than half of 15,849 mouse circRNAs, which are highly abundant, conserved, and dynamically expressed in the brain, are upregulated during the maturation of neurons.
“A study by Rybak et al. demonstrated that more than half of 15,849 mouse circRNAs, which are highly abundant, conserved, and dynamically expressed in the brain, are upregulated during the maturation of neurons [62,65].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [65]
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- Authors
- Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Max Delbrück Center (DE)
- Corresponding author
- Rajewsky, Nikolaus
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 56
- Issue
- 1
- Pages
- 55-66
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2054891772
- Cited by
- 3,083
- References
- 35
- Citations by year
- 2026: 102 · 2025: 199 · 2024: 278 · 2023: 297 · 2022: 382 · 2021: 486 · 2020: 447 · 2019: 332 · 2018: 243 · 2017: 167 · 2016: 81 · 2015: 55 · 2014: 10
- FWCI
- 42.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RA-838/7-1)
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- circular RNA biogenesis, pre-mRNA splicing, introns, neuronal tissue, tissue-specific gene regulation, non-coding RNA
- MeSH terms
- RNA, Circular, Animals, Cells, Cultured, Drosophila, Humans, Models, Genetic, Nuclear Proteins, RNA, RNA Precursors, RNA Splicing, RNA, Messenger, Transcription, Genetic, Drosophila Proteins, HEK293 Cells
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