The Biogenesis of Nascent Circular RNAs
Open accessAbstract
Steady-state circular RNAs (circRNAs) have been mapped to thousands of genomic loci in mammals. We studied circRNA processing using metabolic tagging of nascent RNAs with 4-thiouridine (4sU). Strikingly, the efficiency of circRNA processing from pre-mRNA is extremely low endogenously. Additional studies revealed that back-splicing outcomes correlate with fast RNA Polymerase II elongation rate and are tightly controlled by cis-elements in vivo. Additionally, prolonged 4sU labeling in cells shows that circRNAs are largely processed post-transcriptionally and that circRNAs are stable. Circular RNAs that are abundant at a steady-state level tend to accumulate. This is particularly true in cells, such as neurons, that have slow division rates. This study uncovers features of circRNA biogenesis by investigating the link between nascent circRNA processing and transcription.
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Average RNA Pol II velocity is higher on genes producing circRNAs than on genes not producing circRNAs, and especially on introns of these genes.
“Indeed, the average RNA Pol II velocity is higher on genes producing circRNAs than on genes not producing circRNAs (Zhang et al, 2016) and especially on introns of these genes (Ragan et al, 2019).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Zhang et al, 2016
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 Zhang et al, 2016
Cites
Circular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990 · see citing works
Natural RNA circles function as efficient microRNA sponges
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013) · Nature · doi:10.1038/nature11993 · Cited by 7,985 · see citing works
Circular RNAs are abundant, conserved, and associated with ALU repeats
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013) · RNA · doi:10.1261/rna.035667.112 · Cited by 4,388 · see citing works
circRNA biogenesis competes with pre-mRNA splicing
Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.019 · Cited by 3,083 · see citing works
Exon-intron circular RNAs regulate transcription in the nucleus
Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., et al. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2959 · Cited by 2,905 · see citing works
Self-citationSalzman, J., Gawad, C., Wang, P. L., Lacayo, N. J., & Brown, P. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030733 · Cited by 2,457 · see citing works
Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed
Rybak-Wolf, A., Stottmeister, C., Glažar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.03.027 · Cited by 2,423 · cited 5× · see citing works
“Many such circRNAs are upregulated during neurogenesis (Rybak-Wolf et al., 2015) and are more enriched in synaptogenesis than their linear counterparts (You et al., 2015).”
BackgroundResultInfluentialThe RNA Binding Protein Quaking Regulates Formation of circRNAs
Conn, S. J., Pillman, K. A., Toubia, J., Conn, V. M., Salmanidis, M., Phillips, C. A., Roslan, S., SCHREIBER, A. W., Gregory, P. A., & Goodall, G. J. (2015) · Cell · doi:10.1016/j.cell.2015.02.014 · Cited by 2,187 · see citing works
Complementary Sequence-Mediated Exon Circularization
Zhang, X.-O., Wang, H.-B., Zhang, Y., Lu, X., Chen, L.-L., & Yang, L. (2014) · Cell · doi:10.1016/j.cell.2014.09.001 · Cited by 1,999 · cited 18× · see citing works
“…requires the canonical spliceosomal machinery (Ashwal-Fluss et al., 2014; Starke et al., 2015; Wang and Wang, 2015) and is modulated by both cis- and trans-regulators (Ashwal-Fluss et al., 2014; Zhang et al., 2014; Conn et al., 2015; Ivanov et al., 2015; Kramer et al., 2015; Starke et al., 2015).”
BackgroundMethodInfluentialSelf-citationCell-Type Specific Features of Circular RNA Expression
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003777 · Cited by 1,955 · see citing works
The biogenesis and emerging roles of circular RNAs
Chen, L.-L. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.32 · Cited by 1,743 · see citing works
Self-citationExpanded identification and characterization of mammalian circular RNAs
Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014) · Genome biology · doi:10.1186/s13059-014-0409-z · Cited by 1,578 · see citing works
Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity
You, X., Vlatkovic, I., Babic, A., Will, T., Epstein, I., Tushev, G., Akbalik, G., Wang, M., Glock, C., Quedenau, C., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3975 · Cited by 1,149 · see citing works
Neural progenitors from human embryonic stem cells
Reubinoff, B. E., Itsykson, P., Turetsky, T. T., Pera, M. F., Reinhartz, E., Itzik, A., & Ben‐Hur, T. (2001) · Nature Biotechnology · doi:10.1038/nbt1201-1134 · Cited by 1,121 · see citing works
Analysis of Intron Sequences Reveals Hallmarks of Circular RNA Biogenesis in Animals
Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H. T., Orejuela, M. R., Piechotta, M., Levanon, E. Y., Landthaler, M., Dieterich, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.12.019 · Cited by 1,092 · see citing works
Westholm, J. O., Miura, P., Olson, S., Shenker, S., Joseph, B. J., Sanfilippo, P., Celniker, S., Graveley, B. R., & Lai, E. C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.062 · Cited by 1,001 · see citing works
miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA
Hansen, T. B., Wiklund, E. D., Bramsen, J. B., Villadsen, S. B., Statham, A. L., Clark, S. J., & Kjems, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.359 · Cited by 996 · see citing works
Short intronic repeat sequences facilitate circular RNA productionPreprint
Liang, D., & Wilusz, J. E. (2014) · Genes & Development · doi:10.1101/gad.251926.114 · Cited by 959 · see citing works
Coupling mRNA processing with transcription in time and space
Bentley, D. L. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3662 · Cited by 828 · see citing works
Exon Circularization Requires Canonical Splice Signals
Starke, S., Jost, I., Roßbach, O., Schneider, T. P., Schreiner, S., Hung, L.-H., & Bindereif, A. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.12.002 · Cited by 768 · see citing works
A Slow RNA Polymerase II Affects Alternative Splicing In Vivo
de la Mata, M., Alonso, C. R., Kadener, S., Fededa, J. P., Blaustein, M., Pelisch, F., Cramer, P., Bentley, D., & Kornblihtt, A. R. (2003) · Molecular Cell · doi:10.1016/j.molcel.2003.08.001 · Cited by 683 · see citing works
Efficient backsplicing produces translatable circular mRNAs
Wang, Y., & Wang, Z. (2014) · RNA · doi:10.1261/rna.048272.114 · Cited by 665 · see citing works
Rabani, M., Levin, J. Z., Fan, L., Adiconis, X., Raychowdhury, R., Garber, M., Gnirke, A., Nusbaum, C., Hacohen, N., Friedman, N., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1861 · Cited by 583 · see citing works
Jonkers, I., Kwak, H., & Lis, J. T. (2014) · eLife · doi:10.7554/elife.02407 · Cited by 581 · see citing works
Kramer, M. C., Liang, D., Tatomer, D. C., Gold, B., March, Z. M., Cherry, S. R., & Wilusz, J. E. (2015) · Genes & Development · doi:10.1101/gad.270421.115 · Cited by 494 · see citing works
Bhatt, D. M., Pandya‐Jones, A., Tong, A.-J., Barozzi, I., Lissner, M. M., Natoli, G., Black, D. L., & Smale, S. T. (2012) · Cell · doi:10.1016/j.cell.2012.05.043 · Cited by 442 · see citing works
Genomewide characterization of non-polyadenylated RNAs
Yang, L. C., Duff, M. O., Graveley, B. R., Carmichael, G., & Chen, L. (2011) · Genome biology · doi:10.1186/gb-2011-12-2-r16 · Cited by 423 · see citing works
Self-citationDynamic integration of splicing within gene regulatory pathways
Braunschweig, U., Gueroussov, S., Plocik, A. M., Graveley, B. R., & Blencowe, B. J. (2013) · Cell · doi:10.1016/j.cell.2013.02.034 · Cited by 406 · see citing works
Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate
Fong, N., Kim, H., Zhou, Y., Ji, X., Qiu, J., Saldi, T., Diener, K., Jones, K., Fu, X.-D., & Bentley, D. L. (2014) · Genes & Development · doi:10.1101/gad.252106.114 · Cited by 287 · see citing works
Fuchs, G., Voichek, Y., Benjamin, S., Gilad, S., Amit, I., & Oren, M. (2014) · Genome Biology · doi:10.1186/gb-2014-15-5-r69 · Cited by 203 · see citing works
Tracking Distinct RNA Populations Using Efficient and Reversible Covalent Chemistry
Duffy, E. E., Rutenberg-Schoenberg, M., Stark, C., Kitchen, R. R., Gerstein, M., & Simon, M. D. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.023 · Cited by 193 · see citing works
Rädle, B., Rutkowski, A. J., Ruzsics, Z., Friedel, C. C., Koszinowski, U. H., & Dölken, L. (2013) · Journal of Visualized Experiments · doi:10.3791/50195 · Cited by 93 · see citing works
Chen, T. X., Xiang, J., Zhu, S., Chen, S., Yin, Q.-F., Zhang, X.-O., Zhang, J., Feng, H., Dong, R., Li, X.-J., et al. (2015) · Cell Research · doi:10.1038/cr.2015.24 · Cited by 91 · see citing works
Self-citationRosonina, E., & Blencowe, B. J. (2004) · RNA · doi:10.1261/rna.5207204 · Cited by 71 · see citing works
Characterization of Circular RNAs
Zhang, Y., Yang, L. C., & Chen, L. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-3378-5_17 · Cited by 61 · see citing works
Self-citationFuchs, G., Voichek, Y., Rabani, M., Benjamin, S., Gilad, S., Amit, I., & Oren, M. (2015) · Nature Protocols · doi:10.1038/nprot.2015.035 · Cited by 39 · see citing works
Rädle, B., Rutkowski, A. J., Ruzsics, Z., Friedel, C. C., Koszinowski, U. H., & Dölken, L. (2013) · Journal of Visualized Experiments · doi:10.3791/50195-v · Cited by 25 · see citing works
Fractionation of Non-polyadenylated and Ribosomal-Free RNAs from Mammalian Cells
Yin, Q.-F., Chen, L., & Yang, L. C. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1369-5_6 · Cited by 17 · see citing works
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Kristensen, L. S., Andersen, M. S., Stagsted, L. V. W., Ebbesen, K. K., Hansen, T. B., & Kjems, J. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0158-7 · Cited by 4,823 · see citing works
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Mehta, S. L., Dempsey, R. J., & Vemuganti, R. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101746 · Cited by 281 · see citing works
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Baluapuri, A., Hofstetter, J., Dudvarski Stankovic, N., Endres, T., Bhandare, P., Vos, S. M., Adhikari, B., Schwarz, J. D., Narain, A., Vogt, M., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.031 · Cited by 138 · see citing works
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Uchida, S., Perche, F., Pichon, C., & Cabral, H. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00618 · Cited by 139 · see citing works
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- Authors
- Zhang, Y., Xue, W., Li, X., Zhang, J., Chen, S., Zhang, J.-L., Yang, L., & Chen, L.-L.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Yang, Li
- Chen, Ling-Ling
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 15
- Issue
- 3
- Pages
- 611-624
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2323385078
- Cited by
- 643
- References
- 38
- Citations by year
- 2026: 31 · 2025: 60 · 2024: 65 · 2023: 59 · 2022: 81 · 2021: 130 · 2020: 74 · 2019: 67 · 2018: 39 · 2017: 20 · 2016: 16
- FWCI
- 24.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- 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, circRNA biogenesis, back-splicing, nascent RNA, RNA polymerase II elongation, cis-regulatory elements, post-transcriptional processing, circRNA stability, neurons
- MeSH terms
- RNA, Circular, Base Sequence, Dichlororibofuranosylbenzimidazole, Humans, Neurons, RNA, RNA Polymerase II, RNA Splicing, Thiouridine, Transcription, Genetic, Prosencephalon, Spliceosomes, Sequence Analysis, RNA, Cell Line, Tumor
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