Circular RNAs: New Players in Gene Regulation


The existence of circular RNAs (circRNAs) was demonstrated over 30 years ago. They did not gain much interest at the time because they appeared to be relatively rare when compared to the abundance of the canonical linear RNAs. However, more recent evidence suggests that circRNAs are abundant in cells and tissues and possess intriguing biological properties. These recent developments have renewed our interest in this novel class of molecules. This report will provide an overview of circRNAs, discuss how they may modify our understanding of gene regulation and indicate their most likely relevance to health. The circRNAs from viruses, bacteria and archaea are not in the scope of this report, and we focused this review on circRNAs in eukaryotes.

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Andreeva, K. and Cooper, N. (2015) Circular RNAs: New Players in Gene Regulation. Advances in Bioscience and Biotechnology, 6, 433-441. doi: 10.4236/abb.2015.66043.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Jeck, W.R., Sorrentino, J.A., Wang, K., Slevin, M.K., Burd, C.E., Liu, J., Marzluff, W.F. and Sharpless, N.E. (2013) Circular RNAs Are Abundant, Conserved, and Associated with ALU Repeats. RNA, 19, 141-157.
[2] Jeck, W.R. and Sharpless, N.E. (2014) Detecting and Characterizing Circular RNAs. Nature Biotechnology, 32, 453-461.
[3] 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) Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency. Nature, 495, 333-338.
[4] Salzman, J., Gawad, C., Wang, P.L., Lacayo, N. and Brown, P.O. (2012) Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types. PLoS One, 7, e30733.
[5] Hansen, T.B., Jensen, T.I., Clausen, B.H., Bramsen, J.B., Finsen, B., Damgaard, C.K. and Kjems, J. (2013) Natural RNA Circles Function as Efficient microRNA Sponges. Nature, 495, 384-388.
[6] Houseley, J.M., Garcia-Casado, Z., Pascual, M., Paricio, N., O’Dell, K.M., Monckton, D.G. and Artero, R.D. (2006) Noncanonical RNAs from Transcripts of the Drosophila muscleblind Gene. The Journal of Heredity, 97, 253-260.
[7] Doose, G., Alexis, M., Kirsch, R., Findeiss, S., Langenberger, D., Machne, R., Morl, M., Hoffmann, S. and Stadler, P.F. (2013) Mapping the RNA-Seq Trash Bin: Unusual Transcripts in Prokaryotic Transcriptome Sequencing Data. RNA Biology, 10, 1204-1210.
[8] Vicens, Q. and Westhof, E. (2014) Biogenesis of Circular RNAs. Cell, 159, 13-14.
[9] Wang, P.L., Bao, Y., Yee, M.C., Barrett, S.P., Hogan, G.J., Olsen, M.N., Dinneny, J.R., Brown, P.O. and Salzman, J. (2014) Circular RNA Is Expressed across the Eukaryotic Tree of Life. PLoS One, 9, e95116.
[10] Suzuki, H., Zuo, Y., Wang, J., Zhang, M.Q., Malhotra, A. and Mayeda, A. (2006) Characterization of RNase R-Digested Cellular RNA Source That Consists of Lariat and Circular RNAs from Pre-mRNA Splicing. Nucleic Acids Research, 34, e63.
[11] Guo, J.U., Agarwal, V., Guo, H. and Bartel, D.P. (2014) Expanded Identification and Characterization of Mammalian Circular RNAs. Genome Biology, 15, 409.
[12] Salzman, J., Chen, R.E., Olsen, M.N., Wang, P.L. and Brown, P.O. (2013) Cell-Type Specific Features of Circular RNA Expression. PLoS Genetics, 9, e1003777.
[13] Rybak-Wolf, A., Stottmeister, C., Glazar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., et al. (2015) Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Molecular Cell, 58, 870-885.
[14] Westholm, J.O., Miura, P., Olson, S., Shenker, S., Joseph, B., Sanfilippo, P., Celniker, S.E., Graveley, B.R. and Lai, E.C. (2014) Genome-Wide Analysis of Drosophila Circular RNAs Reveals Their Structural and Sequence Properties and Age-Dependent Neural Accumulation. Cell Reports, 9, 1966-1980.
[15] Ashwal-Fluss, R., Meyer, M., Pamudurti, N.R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N. and Kadener, S. (2014) circRNA Biogenesis Competes with Pre-mRNA Splicing. Molecular Cell, 56, 55-66.
[16] Wang, Y. and Wang, Z. (2015) Efficient Backsplicing Produces Translatable Circular mRNAs. RNA, 21, 172-179.
[17] Kelly, S., Greenman, C., Cook, P.R. and Papantonis, A. (2015) Exon Skipping Is Correlated with Exon Circularization. Journal of Molecular Biology, in press.
[18] Zhang, Y., Zhang, X.O., Chen, T., Xiang, J.F., Yin, Q.F., Xing, Y.H., Zhu, S., Yang, L. and Chen, L.L. (2013) Circular Intronic Long Noncoding RNAs. Molecular Cell, 51, 792-806.
[19] Liang, D. and Wilusz, J.E. (2014) Short Intronic Repeat Sequences Facilitate Circular RNA Production. Genes & Development, 28, 2233-2247.
[20] Conn, S.J., Pillman, K.A., Toubia, J., Conn, V.M., Salmanidis, M., Phillips, C.A., Roslan, S., Schreiber, A.W., Gregory, P.A. and Goodall, G.J. (2015) The RNA Binding Protein Quaking Regulates Formation of circRNAs. Cell, 160, 1125-1134.
[21] Chen, L. and Shan, G. (2015) Circular RNAs Remain Peculiarly Unclear in Biogenesis and Function. Science China Life Sciences, in press.
[22] Gaelle, J.S., Talhouarne, G.J. and Gall, J.G. (2014) Lariat Intronic RNAs in the Cytoplasm of Xenopus tropicalis Oocytes. RNA, 20, 1476-1487.
[23] Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., et al. (2015) Exon-Intron Circular RNAs Regulate Transcription in the Nucleus. Nature Structural & Molecular Biology, 22, 256-264.
[24] You, X., Vlatkovic, I., Babic, A., Will, T., Epstein, I., Tushev, G., Akbalik, G., Wang, M., Glock, C., Quedenau, C., et al. (2015) Neural Cir-cular RNAs Are Derived from Synaptic Genes and Regulated by Development and Plasticity. Nature Neuroscience, 18, 603-610.
[25] Rossi, M., Inoue, S., Walewska, R., Knight, R.A., Dyer, M.J., Cohen, G.M. and Melino, G. (2009) Caspase Cleavage of Itch in Chronic Lymphocytic Leukemia Cells. Biochemical and Biophysical Research Communications, 379, 659-664.
[26] Li, F., Zhang, L., Li, W., Deng, J., Zheng, J., An, M., Lu, J. and Zhou, Y. (2015) Circular RNA ITCH Has Inhibitory Effect on ESCC by Suppressing the Wnt/Beta-Catenin Pathway. Oncotarget, 6, 6001-6013.
[27] Thomas, L.F. and Saetrom, P. (2014) Circular RNAs Are Depleted of Polymorphisms at microRNA Binding Sites. Bioinformatics (Oxford, England), 30, 2243-2246.
[28] Chen, C.Y. and Sarnow, P. (1995) Initiation of Protein Synthesis by the Eukaryotic Translational Apparatus on Circular RNAs. Science, 268, 415-417.
[29] Wilusz, J.E. and Sharp, P.A. (2013) Molecular Biology. A Circuitous Route to Noncoding RNA. Science, 340, 440-441.
[30] Li, P., Chen, S., Chen, H., Mo, X., Li, T., Shao, Y., Xiao, B. and Guo, J. (2015) Using Circular RNA as a Novel Type of Biomarker in the Screening of Gastric Cancer. Clinica Chimica Acta, 444, 132-136.
[31] Bachmayr-Heyda, A., Reiner, A.T., Auer, K., Sukhbaatar, N., Aust, S., Bachleitner-Hofmann, T., Mesteri, I., Grunt, T.W., Zeillinger, R. and Pils, D. (2015) Correlation of Circular RNA Abundance with Proliferation—Exemplified with Colorectal and Ovarian Cancer, Idiopathic Lung Fibrosis, and Normal Human Tissues. Scientific Reports, 5, Article No. 8057.
[32] Burd, C.E., Jeck, W.R., Liu, Y., Sanoff, H.K., Wang, Z. and Sharpless, N.E. (2010) Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk. PLoS Genetics, 6, e1001233.
[33] Hansen, T.B., Kjems, J. and Damgaard, C.K. (2013) Circular RNA and miR-7 in Cancer. Cancer Research, 73, 5609-5612.
[34] Ghosal, S., Das, S., Sen, R., Basak, P. and Chakrabarti, J. (2013) Circ2Traits: A Comprehensive Database for Circular RNA Potentially Associated with Disease and Traits. Frontiers in Genetics, 4, 283.
[35] Costa-Pinheiro, P., Ramalho-Carvalho, J., Vieira, F.Q., Torres-Ferreira, J., Oliveira, J., Goncalves, C.S., Costa, B.M., Henrique, R. and Jeronimo, C. (2015) MicroRNA-375 Plays a Dual Role in Prostate Carcinogenesis. Clinical Epigenetics, 7, 42.
[36] Gong, J., Cui, Z., Li, L., Ma, Q., Wang, Q., Gao, Y. and Sun, H. (2015) MicroRNA-25 Promotes Gastric Cancer Proliferation, Invasion, and Migration by Directly Targeting F-Box and WD-40 Domain Protein 7, FBXW7. Tumor Biology, in press.
[37] Peng, J., Xie, Z., Cheng, L., Zhang, Y., Chen, J., Yu, H., Li, Z. and Kang, H. (2015) Paired Design Study by Real-Time PCR: miR-378* and miR-145 Are Potent Early Diagnostic Biomarkers of Human Colorectal Cancer. BMC Cancer, 15, 158.
[38] Xu, Q., Li, P., Chen, X., Zong, L., Jiang, Z., Nan, L., Lei, J., Duan, W., Zhang, D., Li, X., et al. (2015) miR-221/222 Induces Pancreatic Cancer Progression through the Regulation of Matrix Metalloproteinases. Oncotarget, in press.
[39] Kluiver, J., Gibcus, J.H., Hettinga, C., Adema, A., Richter, M.K., Halsema, N., Slezak-Prochazka, I., Ding, Y., Kroesen, B.J. and van den Berg, A. (2012) Rapid Generation of microRNA Sponges for microRNA Inhibition. PLoS ONE, 7, e29275.
[40] Ebert, M.S., Neilson, J.R. and Sharp, P.A. (2007) Micro-RNA Sponges: Competitive Inhibitors of Small RNAs in Mammalian Cells. Nature Methods, 4, 721-726.
[41] Gentner, B., Schira, G., Giustacchini, A., Amendola, M., Brown, B.D., Ponzoni, M. and Naldini, L. (2009) Stable Knockdown of microRNA in Vivo by Lentiviral Vectors. Nature Methods, 6, 63-66.
[42] Chen, W. and Qin, C. (2015) General Hallmarks of microRNAs in Brain Evolution and Development. RNA Biology, in Press.
[43] Paschon, V., Takada, S.H., Ikebara, J.M., Sousa, E., Raeisossadati, R., Ulrich, H. and Kihara, A.H. (2015) Interplay between Exosomes, microRNAs and Toll-Like Receptors in Brain Disorders. Molecular Neurobiology, in press.
[44] Luo, T., Yin, S., Shi, R., Xu, C., Wang, Y., Cai, J., Yue, Y. and Wu, A. (2015) miRNA Expression Profile and Involvement of Let-7d-APP in Aged Rats with Isoflurane-Induced Learning and Memory Impairment. PLoS ONE, 10, e0119336.
[45] Liu, Y., Chen, S., Zhang, J., Shan, S., Chen, L., Wang, R., Kan, J. and Xu, T. (2015) Analysis of Serum MicroRNAs as Potential Biomarker in Coronary Bifurcation Lesion. Disease Markers, 2015, Article ID: 351015.
[46] Dorn II, G.W. (2015) Great Expectations: MicroRNA-30d and Cardiac Resynchronization Therapy. Circulation, in press.
[47] Das, S. and Halushka, M.K. (2015) Extracellular Vesicle microRNA Transfer in Cardiovascular Disease. Cardiovascular pathology: The Official Journal of the Society for Cardiovascular Pathology, 24, 199-206.
[48] Naghavian, R., Ghaedi, K., Kiani-Esfahani, A., Ganjalikhani-Hakemi, M., Etemadifar, M. and Nasr-Esfahani, M.H. (2015) miR-141 and miR-200a, Revelation of New Possible Players in Modulation of Th17/Treg Differentiation and Pathogenesis of Multiple Sclerosis. PLoS ONE, 10, e0124555.
[49] Schaefer, J.S., Attumi, T., Opekun, A.R., Abraham, B., Hou, J., Shelby, H., Graham, D.Y., Streckfus, C. and Klein, J.R. (2015) MicroRNA Signatures Differentiate Crohn’s Disease from Ulcerative Colitis. BMC Immunology, 16, 5.
[50] Tili, E., Michaille, J.J., Costinean, S. and Croce, C.M. (2008) MicroRNAs, the Immune System and Rheumatic Disease. Nature Clinical Practice Rheumatology, 4, 534-541.
[51] Bahn, J.H., Zhang, Q., Li, F., Chan, T.M., Lin, X., Kim, Y., Wong, D.T. and Xiao, X. (2015) The Landscape of microRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva. Clinical Chemistry, 61, 221-230.

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