Identification and characterization of circular RNAs As a new class of putative biomarkers in human blood
Open accessAbstract
Covalently closed circular RNA molecules (circRNAs) have recently emerged as a class of RNA isoforms with widespread and tissue specific expression across animals, oftentimes independent of the corresponding linear mRNAs. circRNAs are remarkably stable and sometimes highly expressed molecules. Here, we sequenced RNA in human peripheral whole blood to determine the potential of circRNAs as biomarkers in an easily accessible body fluid. We report the reproducible detection of thousands of circRNAs. Importantly, we observed that hundreds of circRNAs are much higher expressed than corresponding linear mRNAs. Thus, circRNA expression in human blood reveals and quantifies the activity of hundreds of coding genes not accessible by classical mRNA specific assays. Our findings suggest that circRNAs could be used as biomarker molecules in standard clinical blood samples.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Transcriptome analysis has been used to identify thousands of circRNAs expressed in peripheral blood mononuclear cells (PBMCs), and circRNAs are expressed at significantly higher levels than corresponding linear mRNAs.
“Transcriptome analysis has been used to identify thousands of circRNAs that are expressed in peripheral blood mononuclear cells (PBMCs), and has shown that circRNAs are expressed at significantly higher levels than corresponding linear mRNAs [33].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
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
Self-citationNatural 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
Self-citationDetecting and characterizing circular RNAs
Jeck, W. R., & Sharpless, N. E. (2014) · Nature Biotechnology · doi:10.1038/nbt.2890 · Cited by 2,685 · see citing works
Long Noncoding RNAs: Cellular Address Codes in Development and Disease
Batista, P. J., & Chang, H. Y. (2013) · Cell · doi:10.1016/j.cell.2013.02.012 · Cited by 2,531 · see citing works
Salzman, 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
The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones
Cech, T. R., & STEITZ, J. A. (2014) · Cell · doi:10.1016/j.cell.2014.03.008 · Cited by 2,456 · 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 6× · see citing works
“Further, as observed in other human samples, we find that most circRNAs are derived from protein coding exonic regions or 5’ UTR sequences (Fig 1c [20],[25]).”
BackgroundResultInfluentialSelf-citationSanger, H. L., Klotz, G., Riesner, D., Gross, H. J., & Kleinschmidt, A. K. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.11.3852 · Cited by 2,296 · see citing works
Circular intronic long noncoding RNAs
Zhang, Y., Zhang, X.-O., Chen, T., Xiang, J.-F., Yin, Q.-F., Xing, Y.-H., Zhu, S., Yang, L., & Chen, L.-L. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.017 · Cited by 2,221 · see citing works
Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis
Li, Y., Zheng, Q., Bao, C., Li, S., Guo, W., Zhao, J., Chen, D., Gu, J., He, X., & Huang, S. (2015) · Cell Research · doi:10.1038/cr.2015.82 · Cited by 2,210 · see citing works
The 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 · see citing works
Cell-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
circBase: a database for circular RNAs
Glažar, P., Papavasileiou, P., & Rajewsky, N. (2014) · RNA · doi:10.1261/rna.043687.113 · Cited by 1,934 · 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
HTSeq – A Python framework to work with high-throughput sequencing dataPreprint
Anders, S., Pyl, P. T., & Huber, W. K. (2014) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/002824 · Cited by 1,286 · see citing works
Mis-splicing yields circular RNA molecules.
Cocquerelle, C., Mascrez, B., Hétuin, D., & Bailleul, B. (1993) · The FASEB Journal · doi:10.1096/fasebj.7.1.7678559 · Cited by 1,197 · 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
Circular transcripts of the testis-determining gene Sry in adult mouse testis
Capel, B., Swain, A., Nicolis, S. K., Hacker, A., Walter, M. A., Koopman, P. A., Goodfellow, P. N., & Lovell-Badge, R. H. (1993) · Cell · doi:10.1016/0092-8674(93)90279-y · Cited by 1,100 · 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
Self-citationShort 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
Burd, C. E., Jeck, W. R., Liu, Y., Sanoff, H. K., Wang, Z., & Sharpless, N. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001233 · Cited by 895 · see citing works
Nigro, J. M., Cho, K. R., Fearon, E. R., Kern, S. E., Ruppert, J. M., Oliner, J., Kinzler, K. W., & Vogelstein, B. (1991) · Cell · doi:10.1016/0092-8674(91)90244-s · Cited by 888 · 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
Circular RNA Is Expressed across the Eukaryotic Tree of Life
Wang, P. L., Bao, Y., Yee, M., Barrett, S. P., Hogan, G. J., Olsen, M. N., Dinneny, J. R., Brown, P. O., & Salzman, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090859 · Cited by 754 · see citing works
The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva
Bahn, J. H., Zhang, Q., Li, F., Chan, T.-M., Lin, X., Kim, Y. D., Wong, D. T., & Xiao, X. G. (2014) · Clinical Chemistry · doi:10.1373/clinchem.2014.230433 · Cited by 658 · see citing works
The hepatitis delta (δ) virus possesses a circular RNA
Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H., & Schellekens, H. (1986) · Nature · doi:10.1038/323558a0 · Cited by 651 · see citing works
Circular RNA (circRNA) in Alzheimer’s disease (AD)
Lukiw, W. J. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00307 · Cited by 636 · see citing works
Transcriptome-wide discovery of circular RNAs in Archaea
Danan, M., Schwartz, S., Edelheit, S., & Sorek, R. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1009 · Cited by 560 · see citing works
Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency
Jens, M. (2014) · Springer theses · doi:10.1007/978-3-319-07082-7_5 · Cited by 444 · see citing works
Splicing with inverted order of exons occurs proximal to large introns.
Cocquerelle, C., Daubersies, P., Majérus, M.-A., Kerckaert, J. P., & Bailleul, B. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05148.x · Cited by 314 · see citing works
Noninvasive in vivo monitoring of tissue-specific global gene expression in humans
Koh, W. L. C., Pan, W., Gawad, C., Fan, H. C., Kerchner, G. A., Wyss‐Coray, T., Blumenfeld, Y. J., El-Sayed, Y. Y., & Quake, S. R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405528111 · Cited by 303 · see citing works
Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping.
Zaphiropoulos, P. G. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6536 · Cited by 245 · see citing works
Grabowski, P. J., Zaug, A. J., & Cech, T. R. (1981) · Cell · doi:10.1016/0092-8674(81)90142-2 · Cited by 196 · see citing works
Zaphiropoulos, P. G. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.6.2985 · Cited by 177 · see citing works
The Mouse formin (Fmn) Gene: Abundant Circular RNA Transcripts and Gene-Targeted Deletion Analysis
Chao, C. W., Chan, D. C., Kuo, A., & Leder, P. (1998) · Molecular Medicine · doi:10.1007/bf03401761 · Cited by 158 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The biogenesis, biology and characterization of circular RNAs
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
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
Widespread and Functional RNA Circularization in Localized Prostate Cancer
Chen, S., Huang, V., Xu, X., Livingstone, J., Soares, F., Jeon, J., Zeng, Y., Hua, J. T., Petricca, J., Guo, H., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.025 · Cited by 544 · see citing works
Hanan, M., Soreq, H., & Kadener, S. (2017) · RNA Biology · doi:10.1080/15476286.2016.1255398 · Cited by 229 · see citing works
Circular RNAs: biogenesis, function, and a role as possible cancer biomarkers
Bolha, L., Ravnik-Glavač, M., & Glavač, D. (2017) · International Journal of Genomics · doi:10.1155/2017/6218353 · Cited by 166 · see citing works
Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential
Gan, H., Lei, Y., Yuan, N., Tang, K., Hao, W., Ma, Q., Wu, M., Zhou, X., Li, X., Huang, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111244 · Cited by 41 · see citing works
Extracellular <scp>RNA</scp> in aging
Dluzen, D. F., Noren Hooten, N., & Evans, M. K. (2017) · WIREs RNA · doi:10.1002/wrna.1385 · Cited by 31 · see citing works
m6A-dependent circular RNA formation mediates tau-induced neurotoxicity
Atrian, F., Ramirez, P., De Mange, J., Marquez, M., Gonzalez, E. M., Minaya, M., Karch, C. M., & Frost, B. (2024) · doi:10.1101/2024.01.25.577211 · Cited by 7 · see citing works
- Authors
- Memczak, S., Papavasileiou, P., Peters, O., & Rajewsky, N.
- Affiliations
- Max Delbrück Center (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Rajewsky, Nikolaus
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-10-20
- Volume
- 10
- Issue
- 10
- Pages
- e0141214
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4617279
- OpenAlex
- W1770991729
- Cited by
- 639
- References
- 42
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 43 · 2023: 49 · 2022: 66 · 2021: 73 · 2020: 106 · 2019: 89 · 2018: 81 · 2017: 57 · 2016: 31
- FWCI
- 24.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- circular RNA, circRNA biomarkers, peripheral blood, blood-based biomarkers, circRNA expression profiling, RNA isoforms, clinical blood samples
- MeSH terms
- RNA, Circular, Brain, Humans, Liver, RNA, Biomarkers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
