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Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed
Open accessAbstract
Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers.
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In the citing paper
“Many circRNAs are significantly upregulated at different time points of neuron maturation in vitro.293”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [293]
In the citing paper
“They are highly expressed in the brain from the embryonic stage to adulthood and substantially upregulated during the differentiation and maturation of neurons.293”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [293]
In the citing paper
“CircRNAs maintain specificity and conservatism in the process of dynamic expression and are highly enriched in the mammalian brain, independent of linear transcripts [62].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [62]
In the citing paper
“CiRS-7 is abundantly expressed in the mammalian brain [49,62], where it increases the translation of the miR-7 target mRNA [14,49].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [62]
In the citing paper
“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 [62]
In the citing paper
“Compared with other cytoplasmic RNAs, circRNAs seem to be more prone to being localized in synapses and their expression is correlated with neural plasticity, which further supports an important function of circRNAs in synaptic transmission [50,62].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [62]
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InfluentialSelf-citationLoss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function
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BackgroundMethodResultInfluentialTranslation and functional roles of circular RNAs in human cancer
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Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity
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“circRNA expression appears to be conserved across mammals (Barrett & Salzman, 2016), and some are even conserved in evolutionarily distant Drosophila (Rybak-Wolf et al., 2015).”
BackgroundInfluentialCircular RNAs: Promising Biomarkers for Human Diseases
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BackgroundInfluentialRETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7
Zeng, K., Chen, X., Xu, M., Liu, X., Hu, X., Xu, T., Sun, H., Pan, Y., He, B., & Wang, S. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0454-8 · Cited by 626
“Circular RNAs (circRNA) are highly conserved and stable covalently closed RNA transcripts generated by back-splicing of a single pre-mRNA with gene-regulatory potential 3,4 .”
BackgroundRetractedN6-Methyladenosine Modification Controls Circular RNA Immunity
Chen, Y. G., Chen, R., Ahmad, S., Verma, R., Kasturi, S. P., Amaya, L., Broughton, J. P., Kim, J., Cadena, C., Pulendran, B., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.016 · Cited by 578
CircHIPK3 sponges miR‐558 to suppress heparanase expression in bladder cancer cells
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“It has been implicated in decreasing circRNA production by weakening and editing RNA duplexes which decreases the likelihood of circularization (Rybak-Wolf et al., 2015).”
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“…and recent deep sequencing studies have expanded this observation to thousands of circular RNAs expressed across eukaryotes, including humans (Salzman et al. 2012; Jeck et al. 2013; Memczak et al. 2013; Guo et al. 2014; Conn et al. 2015; Kelly et al. 2015), mice (Memczak et al. 2013;…”
BackgroundSpatio-temporal regulation of circular RNA expression during porcine embryonic brain development
Venø, M. T., Hansen, T. B., Venø, S. T., Clausen, B. H., Grebing, M., Finsen, B. R., Holm, I. E., & Kjems, J. (2015) · Genome biology · doi:10.1186/s13059-015-0801-3 · Cited by 475
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BackgroundResultSpecific expression and functions of circular RNAs
Mısır, S., Wu, N., & Yang, B. B. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00948-7 · Cited by 493
“The abundance of circRNAs is specific to cell types and tissues during development [7, 8].”
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“However, impaired circRNA biogenesis could be caused by indirect effects of ADAR1.(10,18)”
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BackgroundThe emerging roles and functions of circular RNAs and their generation
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“and intensive accumulation in neural tissues [68].”
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“One study applied BSJ read and normal splicing junction read ratio (named circular-to-linear ratio, CLR) to represent the ratio of circRNA and linear RNA to obtain an overall expression value [93].”
BackgroundA map of human circular RNAs in clinically relevant tissues
Maass, P. G., Glažar, P., Memczak, S., Dittmar, G., Hollfinger, I., Schreyer, L., Sauer, A. V., Toka, O., Aiuti, A., Luft, F. C., et al. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1582-9 · Cited by 391
Self-citationThe Diversity of Long Noncoding RNAs and Their Generation
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CircRNAs: role in human diseases and potential use as biomarkers
Verduci, L., Tarcitano, E., Strano, S., Yarden, Y., & Blandino, G. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03743-3 · Cited by 382
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Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for circRNA Clearance
Lasda, E. L., & Parker, R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148407 · Cited by 382
CircRNA accumulation in the aging mouse brain
Gruner, H. N., Cortés-López, M., Cooper, D. A., Bauer, M. J., & Miura, P. (2016) · Scientific Reports · doi:10.1038/srep38907 · Cited by 366
Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes
Xia, S., Feng, J. Q., Lei, L., Hu, J., Xia, L., Wang, J., Xiang, Y., Liu, L., Zhong, S., Han, L., et al. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw081 · Cited by 368
“We allowed 2 bp window while comparing the backsplice sites as previously described [2].”
BackgroundMethodCircular RNAs open a new chapter in cardiovascular biology
Aufiero, S., Reckman, Y. J., Pinto, Y. M., & Creemers, E. E. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0185-2 · Cited by 355
Review on circular RNAs and new insights into their roles in cancer
Tang, X., Ren, H., Guo, M., Qian, J., Yang, Y., & Gu, C. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.01.018 · Cited by 358
Screening for functional circular RNAs using the CRISPR–Cas13 system
Li, S., Li, X., Xue, W., Zhang, L., Yang, L.-Z., Cao, S.-M., Lei, Y.-N., Liu, C.-X., Guo, S.-K., Shan, L., et al. (2020) · Nature Methods · doi:10.1038/s41592-020-01011-4 · Cited by 365
CircNet: a database of circular RNAs derived from transcriptome sequencing data
Liu, Y., Li, J., Sun, C.-H., Andrews, E. H., Chao, R.-F., Lin, F.-M., Weng, S.-L., Hsu, S., Huang, C., Cheng, C., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv940 · Cited by 342
“CircRNAs functional correlation with brain function, synaptic plasticity (26,27) and fetal development (28) has recently been reported.”
BackgroundMolecular roles and function of circular RNAs in eukaryotic cells
Holdt, L. M., Kohlmaier, A., & Teupser, D. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2688-5 · Cited by 347
“CircRNAs have been found to be particularly enriched in neuronal tissues of different organisms ranging from Dros‐ ophila to humans [29, 30, 44, 77, 131].”
BackgroundInfluentialDenzler, R., McGeary, S. E., Title, A. C., Agarwal, V., Bartel, D. P., & Stoffel, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.09.027 · Cited by 340
“However, very few other circRNAs have more miRNA-binding sites than expected by chance (Guo et al., 2014; Rybak-Wolf et al., 2015), which brings the focus back to linear transcripts as a more abundant source of potential ceRNA candidates.”
BackgroundCircACC1 Regulates Assembly and Activation of AMPK Complex under Metabolic Stress
Li, Q., Wang, Y., Wu, S., Zhou, Z., Ding, X., Shi, R., Thorne, R. F., Zhang, X. D., Hu, W., & Wu, M. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.009 · Cited by 344
The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency
Yu, C.-Y., Li, T.-C., Wu, Y.-Y., Yeh, C.-H., Chiang, W., Chuang, C.-Y., & Kuo, H.-C. (2017) · Nature Communications · doi:10.1038/s41467-017-01216-w · Cited by 336
Dou, Y., Cha, D. J., Franklin, J. L., Higginbotham, J. N., Jeppesen, D. K., Weaver, A. M., Prasad, N., Levy, S., Coffey, R. J., Patton, J. G., et al. (2016) · Scientific Reports · doi:10.1038/srep37982 · Cited by 331
Circular RNA mediates cardiomyocyte death via miRNA-dependent upregulation of MTP18 expression
Wang, K., Gan, T.-Y., Li, N., Liu, C.-Y., Zhou, L., Gao, J.-N., Chen, C., Yan, K.-W., Ponnusamy, M., Zhang, Y.-H., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.61 · Cited by 324
Chen, X., Mao, R., Su, W., Yang, X., Geng, Q., Guo, C., Wang, Z., Wang, J., Kresty, L. A., Beer, D. G., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1634945 · Cited by 322
Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications
Cheng, J., Meng, J., Zhu, L., & Peng, Y. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01189-3 · Cited by 318
Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease
Piwecka, M., Rajewsky, N., & Rybak-Wolf, A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00809-y · Cited by 320
Self-citationThe pro-metastasis effect of circANKS1B in breast cancer
Zeng, K., He, B., Yang, B. B., Xu, T., Chen, X., Xu, M., Liu, X., Sun, H., Pan, Y., & Wang, S. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0914-x · Cited by 324
Lessons from non-canonical splicing
Sibley, C. R., Blázquez, L., & Ule, J. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.46 · Cited by 327
Structured elements drive extensive circular RNA translation
Chen, C., Cheng, R., Demeter, J., Chen, J., Weingarten-Gabbay, S., Jiang, L., Snyder, M. P., Weissman, J. S., Segal, E., Jackson, P. K., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.042 · Cited by 323
“Because circRNAs are expressed in a tissue-specific and cell line-specific manner (Rybak-Wolf et al., 2015), to accurately estimate the circORF discovery rate (the number of circORFs detected in each dataset), we consider the IRES-containing circRNAs expressed in the corresponding cell line as the denominator.”
BackgroundBiogenesis and Functions of Circular RNAs Come into Focus
Xiao, M., Ai, Y., & Wilusz, J. E. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.12.004 · Cited by 316
Lu, Q., Liu, T., Feng, H., Yang, R., Zhao, X., Chen, W., Jiang, B., Qin, H., Guo, X., Liu, M., et al. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1040-0 · Cited by 313
“Salient features of circRNAs include significant stability, high abundance, evolutionary conservation, and tissue-specific expression [9, 10].”
BackgroundCircular RNA: An emerging non-coding RNA as a regulator and biomarker in cancer
Chen, B., & Huang, S. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.011 · Cited by 310
Biogenesis and Regulatory Roles of Circular RNAs
Yang, L. C., Wilusz, J. E., & Chen, L. (2022) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120420-125117 · Cited by 308
CircNT5E Acts as a Sponge of miR-422a to Promote Glioblastoma Tumorigenesis
Wang, R., Zhang, S., Chen, X., Li, N., Li, J., Jia, R., Pan, Y., & Liang, H. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0532 · Cited by 299
“Two important studies revealed that the RNA-editing enzyme ADAR1 is involved in circRNA biogenesis and that its knockdown may significantly upregulate circRNA expression in human HEK293 cells and SH-SY5Y cells (41, 45).”
BackgroundResultChen, G., Shi, Y., Liu, M., & Sun, J. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0204-3 · Cited by 297
Circular RNAs: a new frontier in the study of human diseases
Chen, Y., Li, C., Tan, C., & Liu, X. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2016-103758 · Cited by 296
“Rybak-Wolf et al 42 examined 29 human/mouse RNA sequencing datasets from dissected brain tissues or neuronal-differentiated cell lines.”
BackgroundComprehensive identification of internal structure and alternative splicing events in circular RNAs
Gao, Y., Wang, J., Zheng, Y., Zhang, J., Chen, S., & Zhao, F. (2016) · Nature Communications · doi:10.1038/ncomms12060 · Cited by 290
Circular RNAs in immune responses and immune diseases
Chen, X., Yang, T., Wang, W., Xi, W., Zhang, T., Li, Q., Yang, A., & Wang, T. (2019) · Theranostics · doi:10.7150/thno.29678 · Cited by 293
Circular RNA: an emerging key player in RNA world
Meng, X., Li, X., Zhang, P., Wang, J., Zhou, Y., & Chen, M. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw045 · Cited by 294
Role of circular RNAs in brain development and CNS diseases
Mehta, S. L., Dempsey, R. J., & Vemuganti, R. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101746 · Cited by 281
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript PRR11 proline-rich protein 11 RBPs RNA binding proteins RNA-FISH RNA fluorescence in situ hybridization ROS reactive oxygen species SCI spinal cord injury SIRT1 Sirtuin 1 SMN1 survival motor neuron 1 SOX13 SRY-Box 13 SRSF1 serine and argin…”
BackgroundInfluentialDong, R., Ma, X.-K., Li, G., & Yang, L. C. (2018) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2018.08.001 · Cited by 278
“Although generally expressed at low levels, circRNAs are highly enriched in brains/neurons [18,23,31].”
BackgroundInfluentialCircular RNAs: A Novel Class of Functional RNA Molecules with a Therapeutic Perspective
Santer, L., Bär, C., & Thum, T. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.07.001 · Cited by 279
“ADAR expression level negatively correlates with several circRNAs.(30,31) More recently, it was described that the RNA helicase DHX9 (DExH-Box Helicase 9), which binds double-stranded RNA (dsRNA), is involved in the”
BackgroundCircular RNA BCRC-3 suppresses bladder cancer proliferation through miR-182-5p/p27 axis
Xie, F., Li, Y., Wang, M., Huang, C., Tao, D., Zheng, F., Zhang, H., Zeng, F., Xiao, X., & Jiang, G. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0892-z · Cited by 274
circPTN sponges miR-145-5p/miR-330-5p to promote proliferation and stemness in glioma
Chen, J., Chen, T., Zhu, Y., Li, Y., Zhang, Y., Wang, Y., Li, X., Xie, X., Wang, J., Huang, M., et al. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1376-8 · Cited by 268
Metadata
- Authors
- Rybak-Wolf, A., Stottmeister, C., Glažar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., Herzog, M., Schreyer, L., Papavasileiou, P., Ivanov, A., Öhman, M., Refojo, D., Kadener, S., & Rajewsky, N.
- Affiliations
- Max Delbrück Center (DE)
- Max Planck Institute of Psychiatry (DE)
- Hebrew University of Jerusalem (IL)
- Stockholm University (SE)
- Corresponding author
- Rajewsky, Nikolaus
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 58
- Issue
- 5
- Pages
- 870-885
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1991082489
- Semantic Scholar
- 2d5cc6120582eee013b4aab9138fa48d35f384f1
- Cited by
- 2,423
- References
- 40
- Citations by year
- 2026: 68 · 2025: 143 · 2024: 238 · 2023: 246 · 2022: 312 · 2021: 358 · 2020: 344 · 2019: 284 · 2018: 203 · 2017: 122 · 2016: 74 · 2015: 23
- FWCI
- 61.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Americanae (AECID Library) (publishedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- 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, mammalian brain, neuronal differentiation, synapses, ADAR1, RNA editing, Drosophila brain, circRNA biomarkers
- MeSH terms
- RNA, Circular, Animals, Base Sequence, Brain, Cell Line, Drosophila melanogaster, Humans, Molecular Sequence Data, Organ Specificity, RNA, RNA, Messenger, Synapses, Sequence Analysis, DNA, Mice, Neurogenesis
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