Multifaceted roles of complementary sequences on circRNA formation

Abstract

Background: Circular RNAs (circRNAs) from back-spliced exon(s) are characterized by the covalently closed loop feature with neither 5′ to 3′ polarity nor polyadenylated tail. By using specific computational approaches that identify reads mapped to back-splice junctions with a reversed genomic orientation, ten thousands of circRNAs have been recently re-identified in various cell lines/tissues and across different species. Increasing lines of evidence suggest that back-splicing is catalyzed by the canonical spliceosomal machinery and modulated by cis-elements and trans-factors.

Results: In this mini-review, we discuss our current understanding of circRNA biogenesis regulation, mainly focusing on the complex regulation of complementary sequences, especially Alus in human, on circRNA formation.

Conclusions: Back-splicing can be significantly facilitated by RNA pair formed by orientation-opposite complementary sequences that juxtapose flanking introns of circularized exon(s). RNA pair formed within individual introns competes with RNA pair formed across flanking introns in the same gene locus, leading to distinct choices for either canonical splicing or back-splicing. Multiple RNA pairs that bracket different circle-forming exons compete for alternative back-splicing selection, resulting in multiple circRNAs generated in a single gene locus.

Graphical abstract

Keywords

circRNA / circRNA biogenesis / back-splicing / cis-elements / complementary sequences / Alu

References

[1] Chen, L. L. (2016) The biogenesis and emerging roles of circular RNAs. Nat. Rev. Mol. Cell Biol., 17, 205–211

[2] Chen, L. L. and Yang, L. (2015) Regulation of circRNA biogenesis. RNA Biol., 12, 381–388

[3] Lasda, E. and Parker, R. (2014) Circular RNAs: diversity of form and function. RNA, 20, 1829–1842

[4] Yang, L. (2015) Splicing noncoding RNAs from the inside out. WIREs RNA, 6, 651–660

[5] 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. Mol. Cell, 51, 792–806

[6] 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

[7] Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495, 333–338

[8] 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 Genet., 9, e1003777

[9] 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

[10] Zhang, X. O., Wang, H. B., Zhang, Y., Lu, X., Chen, L. L. and Yang, L. (2014) Complementary sequence-mediated exon circularization. Cell, 159, 134–147

[11] Yang, L., Duff, M. O., Graveley, B. R., Carmichael, G. G. and Chen, L. L. (2011) Genomewide characterization of non-polyadenylated RNAs. Genome Biol., 12, R16

[12] Yin, Q. F., Chen, L. L. and Yang, L. (2015) Fractionation of non-polyadenylated and ribosomal-free RNAs from mammalian cells. Methods Mol. Biol., 1206, 69–80

[13] Zhang, Y., Yang, L. and Chen, L. L. (2016) Characterization of Circular RNAs. Methods Mol. Biol., 1402, 215–227

[14] Chen, L. L. and Yang, L. (2017) ALUternative regulation for gene expression. Trends Cell Biol., 27, 480–490

[15] Hansen, T. B., Veno, M. T., Damgaard, C. K. and Kjems, J. (2016) Comparison of circular RNA prediction tools. Nucleic Acids Res., 44, e58

[16] Zhang, X. O., Dong, R., Zhang, Y., Zhang, J. L., Luo, Z., Zhang, J., Chen, L. L. and Yang, L. (2016) Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res., 26, 1277–1287

[17] Jeck, W. R. and Sharpless, N. E. (2014) Detecting and characterizing circular RNAs. Nat. Biotechnol., 32, 453–461

[18] Dong, R., Ma, X. K., Chen, L. L. and Yang, L. (2016) Increased complexity of circRNA expression during species evolution. RNA Biol., 1–11. doi: 10.1080/15476286.2016.1269999

[19] Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H. T., Orejuela, M. R., Piechotta, M., Levanon, E. Y., Landthaler, M., Dieterich, C., (2015) Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep., 10, 170–177

[20] Rybak-Wolf, A., Stottmeister, C., Glazar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol. Cell, 58, 870–885

[21] 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 Rep., 9, 1966–1980

[22] 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. Mol. Cell, 56, 55–66

[23] Starke, S., Jost, I., Rossbach, O., Schneider, T., Schreiner, S., Hung, L. H. and Bindereif, A. (2015) Exon circularization requires canonical splice signals. Cell Rep., 10, 103–111

[24] Zhang, Y., Xue, W., Li, X., Zhang, J., Chen, S., Zhang, J. L., Yang, L. and Chen, L. L. (2016) The biogenesis of nascent circular RNAs. Cell Rep., 15, 611–624

[25] Liang, D. and Wilusz, J. E. (2014) Short intronic repeat sequences facilitate circular RNA production. Genes Dev., 28, 2233–2247

[26] Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921

[27] Chen, L. L., DeCerbo, J. N. and Carmichael, G. G. (2008) Alu element—mediated gene silencing. EMBO J., 27, 1694–1705

[28] Guarnerio, J., Bezzi, M., Jeong, J. C., Paffenholz, S. V., Berry, K., Naldini, M. M., Lo-Coco, F., Tay, Y., Beck, A. H. and Pandolfi, P. P. (2016) Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell, 165, 289–302

[29] 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

[30] Kramer, M. C., Liang, D., Tatomer, D. C., Gold, B., March, Z. M., Cherry, S. and Wilusz, J. E. (2015) Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev., 29, 2168–2182

[31] Castello, A., Fischer, B., Eichelbaum, K., Horos, R., Beckmann, B. M., Strein, C., Davey, N. E., Humphreys, D. T., Preiss, T., Steinmetz, L. M., (2012) Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell, 149, 1393–1406

[32] He, C., Sidoli, S., Warneford-Thomson, R., Tatomer, D. C., Wilusz, J. E., Garcia, B. A. and Bonasio, R. (2016) High-resolution mapping of RNA-binding regions in the nuclear proteome of embryonic stem cells. Mol. Cell, 64, 416–430

[33] Li, X., Liu, C. X., Xue, W., Zhang, Z., Jiang, S., Yin, Q. F., Wei, J., Yao, R. W., Yang, L. and Chen, L. L. (2017) Coordinated circRNA biogenesis and function with NF90/NF110 in viral infection. Mol. Cell, 67，214-227.e7.

[34] Aktaş T., Avşar Ilık, İ., Maticzka, D., Bhardwaj, V., Pessoa Rodrigues, C., Mittler, G., Manke, T., Backofen, R. and Akhtar, A. (2017) DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature, 544, 115–119

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