Abstract
Circular RNAs (circRNAs) are covalently closed single-stranded RNAs with regulatory activity and regarded as new types of therapeutic targets in diseases such as cancers. By means of RNA-Seq technology, numerous cardiac circRNAs were discovered. Although some candidates were detected to involve in heart disease in murine model, relative low sequence conservation and expression level of their human homologs might result in an insignificant, even distinct effect in the human heart. Therefore, the therapeutic significance of circRNAs should be more strictly considered. It is also necessary to discuss which circRNA is suitable for being applied in heart disease treatment. Here, we are willing to introduce a ~ 1830 nt circular transcript generated from single exon of sodium/calcium exchanger 1 (ncx1) gene (also called solute carrier family 8 member A1, slc8a1), usually named circNCX1 or circSLC8A1, which is gradually coming into our view. circNCX1 is one of the most cardiac-enriched circRNAs. It is widely existent in vertebrate and relatively conserved, indicating its indispensability during the evolution of species. Indeed, circNCX1 was shown to involve in heart development by some expression analysis. It was further revealed that the dysregulation of circNCX1 is one of the key pathogeneses of heart diseases including ischemic cardiac injury and hypertrophic cardiomyopathy. To make the significance of circNCX1 in the heart clear, we comprehensively dissected circNCX1 in the aspects of its parental gene structure, conservation, biogenesis and expression profiles, function, molecular mechanisms, and clinical application in this review. New medicine or therapeutic schedules based on circNCX1 are expected in the future.
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Change history
22 November 2021
A Correction to this paper has been published: https://doi.org/10.1007/s12265-021-10183-z
Abbreviations
- Ago2:
-
Argonaute 2
- CELF1:
-
CUGBP Elav-like family member 1
- ChIP-seq:
-
Chromatin immunoprecipitation and sequencing
- circRNAs:
-
Circular RNAs
- HIF1α:
-
Hypoxia-inducible factor 1α
- HDAC:
-
Histone deacetylase
- hnRNAs:
-
Heterogeneous nuclear RNAs
- hESCs:
-
Human embryonic stem cells
- iPSC:
-
Induced pluripotent stem cells
- I/R:
-
Myocardial ischemia–reperfusion
- MI:
-
Myocardial infarction
- MBNL1:
-
Muscleblind-like protein 1
- ncx1:
-
Sodium/calcium exchanger 1
- ORF:
-
Open reading frame
- PTBP1:
-
Polypyrimidine tract-binding protein 1
- PD:
-
Parkinson’s disease
- RBP:
-
RNA-binding protein
- slc8a1:
-
Solute carrier family 8 member A1
- SEs:
-
Super enhancers
- SINEs:
-
Short interspersed repeat segments
- SRSF:
-
Serine-/arginine-rich splicing factor
References
Akazawa, H., & Komuro, I. (2003). Roles of cardiac transcription factors in cardiac hypertrophy. Circulation Research, 92, 1079–1088. https://doi.org/10.1161/01.RES.0000072977.86706.23.
Hannan, R., Jenkins, A., Jenkins, A., & Brandenburger, Y. (2003). Cardiac hypertrophy: A matter of translation. Clinical and Experimental Pharmacology and Physiology, 30, 517–527. https://doi.org/10.1046/j.1440-1681.2003.03873.x
Preissl, S., Schwaderer, M., Raulf, A., Hesse, M., Gruning, B. A., Kobele, C., et al. (2015). Deciphering the epigenetic code of cardiac myocyte transcription. Circulation Research, 117, 413–423. https://doi.org/10.1161/CIRCRESAHA.115.306337.
Papait, R., Serio, S., Pagiatakis, C., Rusconi, F., Carullo, P., Mazzola, M., Salvarani, N., Miragoli, M., & Condorelli, G. (2017). Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy. Circulation, 136, 1233–1246. https://doi.org/10.1161/circulationaha.117.028561
Poller, W., Dimmeler, S., Heymans, S., Zeller, T., Haas, J., Karakas, M., Leistner, D. M., Jakob, P., Nakagawa, S., Blankenberg, S., Engelhardt, S., Thum, T., Weber, C., Meder, B., Hajjar, R., & Landmesser, U. (2018). Non-coding RNAs in cardiovascular diseases: Diagnostic and therapeutic perspectives. European Heart Journal, 39, 2704–2716. https://doi.org/10.1093/eurheartj/ehx165
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 19, 141–157. https://doi.org/10.1261/rna.035667.112
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., Loewer, A., Ziebold, U., Landthaler, M., Kocks, C., le Noble, F., & Rajewsky, N. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495, 333–338. https://doi.org/10.1038/nature11928
Chen, L. L. (2016). The biogenesis and emerging roles of circular RNAs. Nature Reviews Molecular Cell Biology, 17, 205–211. https://doi.org/10.1038/nrm.2015.32
Suzuki, H., Zuo, Y., Wang, J., Zhang, M. Q., Malhotra, A., & 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. https://doi.org/10.1093/nar/gkl151.
Holdt, L. M., Stahringer, A., Sass, K., Pichler, G., Kulak, N. A., Wilfert, W., et al. (2016). Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nature Communications, 7, 12429. https://doi.org/10.1038/ncomms12429.
Du, W. W., Yang, W., Liu, E., Yang, Z., Dhaliwal, P., & Yang, B. B. (2016). Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Research, 44, 2846–2858. https://doi.org/10.1093/nar/gkw027
Du, W., Fang, L., Yang, W., Wu, N., Awan, F., Yang, Z., & Yang, B. B. (2017). Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death and Differentiation, 24, 357–370. https://doi.org/10.1038/cdd.2016.133
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495, 384–388. https://doi.org/10.1038/nature11993
Zhang, Y., Zhang, X. O., Chen, T., Xiang, J. F., Yin, Q. F., Xing, Y. H., Zhu, S., Yang, L., & Chen, L. L. (2013). Circular intronic long noncoding RNAs. Molecular Cell, 51, 792–806. https://doi.org/10.1016/j.molcel.2013.08.017
Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., Zhu, P., Chang, Z., Wu, Q., Zhao, Y., Jia, Y., Xu, P., Liu, H., & Shan, G. (2015). Exon-intron circular RNAs regulate transcription in the nucleus. Nature Structure and Molecular Biology, 22, 256–264. https://doi.org/10.1038/nsmb.2959
Pamudurti, N. R., Bartok, O., Jens, M., Ashwal-Fluss, R., Stottmeister, C., Ruhe, L., Hanan, M., Wyler, E., Perez-Hernandez, D., Ramberger, E., Shenzis, S., Samson, M., Dittmar, G., Landthaler, M., Chekulaeva, M., & Rajewsky N,&Kadener S, . (2017). Translation of CircRNAs. Molecular Cell, 66(9–21), e27. https://doi.org/10.1016/j.molcel.2017.02.021
Legnini, I., Di Timoteo, G., Rossi, F., Morlando, M., Briganti, F., Sthandier, O., Fatica, A., Santini, T., Andronache, A., Wade, M., Laneve, P., Rajewsky, N., & Bozzoni, I. (2017). Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Molecular Cell, 66(22–37), e29. https://doi.org/10.1016/j.molcel.2017.02.017
Liang, W., Wong, C., Liang, P., Shi, M., Cao, Y., Rao, S., Tsui, S., Waye, M., Zhang, Q., Fu, W., & Zhang, J. (2019). Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biology, 20, 84. https://doi.org/10.1186/s13059-019-1685-4
Yang Y, Gao X, Zhang M, Yan S, Sun C, Xiao F, Huang N, Yang X, Zhao K, Zhou H, Huang S, Xie B, & Zhang N (2018) Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. Journal of the National Cancer Institute 110
Zhang, M., Zhao, K., Xu, X., Yang, Y., Yan, S., Wei, P., Liu, H., Xu, J., Xiao, F., Zhou, H., Yang, X., Huang, N., Liu, J., He, K., Xie, K., Zhang, G., Huang, S., & Zhang, N. (2018). A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nature Communications, 9, 4475. https://doi.org/10.1038/s41467-018-06862-2
Xia, X., Li, X., Li, F., Wu, X., Zhang, M., Zhou, H., Huang, N., Yang, X., Xiao, F., Liu, D., Yang, L., & Zhang, N. (2019). A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1. Molecular Cancer, 18, 131. https://doi.org/10.1186/s12943-019-1056-5
Zhang, M., Huang, N., Yang, X., Luo, J., Yan, S., Xiao, F., Chen, W., Gao, X., Zhao, K., Zhou, H., Li, Z., Ming, L., Xie, B., & Zhang, N. (2018). A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene, 37, 1805–1814. https://doi.org/10.1038/s41388-017-0019-9
Li, J., Ma, M., Yang, X., Zhang, M., Luo, J., Zhou, H., Huang, N., Xiao, F., Lai, B., Lv, W., & Zhang, N. (2020). Circular HER2 RNA positive triple negative breast cancer is sensitive to pertuzumab. Molecular Cancer, 19, 142. https://doi.org/10.1186/s12943-020-01259-6
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N., & Brown, P. O. (2012). Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS ONE, 7, e30733. https://doi.org/10.1371/journal.pone.0030733
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013). Cell-type specific features of circular RNA expression. PLoS Genetics, 9, e1003777. https://doi.org/10.1371/journal.pgen.1003777
Werfel, S., Nothjunge, S., Schwarzmayr, T., Strom, T. M., Meitinger, T., & Engelhardt, S. (2016). Characterization of circular RNAs in human, mouse and rat hearts. Journal of Molecular and Cellular Cardiology, 98, 103–107. https://doi.org/10.1016/j.yjmcc.2016.07.007
Tan, W. L., Lim, B. T., Anene-Nzelu, C. G., Ackers-Johnson, M., Dashi, A., See, K., Tiang, Z., Lee, D. P., Chua, W. W., Luu, T. D., Li, P. Y., Richards, A. M., & Foo, R. S. (2017). A landscape of circular RNA expression in the human heart. Cardiovascular Research, 113, 298–309. https://doi.org/10.1093/cvr/cvw250
Wang, K., Long, B., Liu, F., Wang, J. X., Liu, C. Y., Zhao, B., Zhou, L. Y., Sun, T., Wang, M., Yu, T., Gong, Y., Liu, J., Dong, Y. H., Li, N., & Li, P. F. (2016). A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. European Heart Journal, 37, 2602–2611. https://doi.org/10.1093/eurheartj/ehv713
Zhou, L. Y., Zhai, M., Huang, Y., Xu, S., An, T., Wang, Y. H., Zhang, R. C., Liu, C. Y., Dong, Y. H., Wang, M., Qian, L. L., Ponnusamy, M., Zhang, Y. H., Zhang, J., & Wang, K. (2019). The circular RNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway. Cell death and differentiation, 26, 1299–1315. https://doi.org/10.1038/s41418-018-0206-4
Du, W. W., Yang, W., Chen, Y., Wu, Z. K., Foster, F. S., Yang, Z., Li, X., & Yang, B. B. (2017). Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. European Heart Journal, 38, 1402–1412. https://doi.org/10.1093/eurheartj/ehw001
Rybak-Wolf, A., Stottmeister, C., Glazar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., Herzog, M., Schreyer, L., Papavasileiou, P., Ivanov, A., Ohman, M., Refojo, D., Kadener, S., & Rajewsky, N. (2015). Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Molecular Cell, 58, 870–885. https://doi.org/10.1016/j.molcel.2015.03.027
Maass, P. G., Glazar, P., Memczak, S., Dittmar, G., Hollfinger, I., Schreyer, L., Sauer, A. V., Toka, O., Aiuti, A., Luft, F. C., & Rajewsky, N. (2017). A map of human circular RNAs in clinically relevant tissues. Journal of Molecular Medicine (Berlin), 95, 1179–1189. https://doi.org/10.1007/s00109-017-1582-9
Thomson DW,&Dinger ME, . (2016). Endogenous microRNA sponges: Evidence and controversy. Nature Reviews Genetics, 17, 272–283. https://doi.org/10.1038/nrg.2016.20
Li XF,&Lytton J, . (1999). A circularized sodium-calcium exchanger exon 2 transcript. Journal of Biological Chemistry, 274, 8153–8160. https://doi.org/10.1074/jbc.274.12.8153
Ouyang, H., Chen, X., Wang, Z., Yu, J., Jia, X., Li, Z., Luo, W., Abdalla, B. A., Jebessa, E., Nie, Q., & Zhang, X. (2018). Circular RNAs are abundant and dynamically expressed during embryonic muscle development in chickens. DNA Research, 25, 71–86. https://doi.org/10.1093/dnares/dsx039
Sai, L., Li, L., Hu, C., Qu, B., Guo, Q., Jia, Q., Zhang, Y., Bo, C., Li, X., Shao, H., Ng, J. C., & Peng, C. (2018). Identification of circular RNAs and their alterations involved in developing male Xenopus laevis chronically exposed to atrazine. Chemosphere, 200, 295–301. https://doi.org/10.1016/j.chemosphere.2018.02.140
Sharma, D., Sehgal, P., Mathew, S., Vellarikkal, S. K., Singh, A. R., Kapoor, S., Jayarajan, R., & ScariaSivasubbu, V. S. (2019). A genome-wide map of circular RNAs in adult zebrafish. Scientific Reports, 9, 3432. https://doi.org/10.1038/s41598-019-39977-7
Jakobi T, Siede D, Eschenbach J, Heumuller AW, Busch M, Nietsch R, Meder B, Most P, Dimmeler S, Backs J, Katus HA, & Dieterich C (2020) Deep characterization of circular RNAs from human cardiovascular cell models and cardiac tissue. Cells 9https://doi.org/10.3390/cells9071616
Li, M., Ding, W., Tariq, M. A., Chang, W., Zhang, X., Xu, W., Hou, L., Wang, Y., & Wang, J. (2018). A circular transcript of ncx1 gene mediates ischemic myocardial injury by targeting miR-133a-3p. Theranostics, 8, 5855–5869. https://doi.org/10.7150/thno.27285
Lim, T. B., Aliwarga, E., Luu, T. D. A., Li, Y. P., Ng, S. L., Annadoray, L., Sian, S., Ackers-Johnson, M. A., & Foo, R. S. (2019). Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy. Cardiovascular Research, 115, 1998–2007. https://doi.org/10.1093/cvr/cvz130
Szabo, L., Morey, R., Palpant, N. J., Wang, P. L., Afari, N., Jiang, C., Parast, M. M., Murry, C. E., Laurent, L. C., & Salzman, J. (2015). Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biology, 16, 126. https://doi.org/10.1186/s13059-015-0690-5
Lei, W., Feng, T., Fang, X., Yu, Y., Yang, J., Zhao, Z. A., Liu, J., Shen, Z., Deng, W., & Hu, S. (2018). Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes. Stem Cell Research and Therapy, 9, 56. https://doi.org/10.1186/s13287-018-0793-5
Siede, D., Rapti, K., Gorska, A. A., Katus, H. A., Altmuller, J., Boeckel, J. N., Meder, B., Maack, C., Volkers, M., Muller, O. J., Backs, J., & Dieterich, C. (2017). Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease. Journal of Molecular and Cellular Cardiology, 109, 48–56. https://doi.org/10.1016/j.yjmcc.2017.06.015
Humphreys, D. T., Fossat, N., Demuth, M., Tam, P. P. L., & Ho, J. W. K. (2019). Ularcirc: Visualization and enhanced analysis of circular RNAs via back and canonical forward splicing. Nucleic Acids Research, 47, e123. https://doi.org/10.1093/nar/gkz718
Dong, H., Dunn, J., & Lytton, J. (2002). Electrophysiological studies of the cloned rat cardiac NCX1.1 in transfected HEK cells: A focus on the stoichiometry. Annals of the New York Academy of Sciences, 976, 159–165. https://doi.org/10.1111/j.1749-6632.2002.tb04737.x
Wakimoto, K., Kobayashi, K., Kuro, O. M., Yao, A., Iwamoto, T., Yanaka, N., Kita, S., Nishida, A., Azuma, S., Toyoda, Y., Omori, K., Imahie, H., Oka, T., Kudoh, S., Kohmoto, O., Yazaki, Y., Shigekawa, M., Imai, Y., Nabeshima, Y., & Komuro, I. (2000). Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. Journal of Biological Chemistry, 275, 36991–36998. https://doi.org/10.1074/jbc.M004035200
Komuro, I., Wenninger, K. E., Philipson, K. D., & Izumo, S. (1992). Molecular cloning and characterization of the human cardiac Na+/Ca2+ exchanger cDNA. Proc Natl Acad Sci U S A, 89, 4769–4773. https://doi.org/10.1073/pnas.89.10.4769
Kofuji, P., Hadley, R. W., Kieval, R. S., Lederer, W. J., & Schulze, D. H. (1992). Expression of the Na-Ca exchanger in diverse tissues: A study using the cloned human cardiac Na-Ca exchanger. American Journal of Physiology, 263, C1241-1249. https://doi.org/10.1152/ajpcell.1992.263.6.C1241
Fagerberg, L., Hallstrom, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., Asplund, A., Sjostedt, E., Lundberg, E., Szigyarto, C. A., Skogs, M., Takanen, J. O., Berling, H., Tegel, H., Mulder, J., … Uhlen, M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular and Cellular Proteomics, 13, 397–406. https://doi.org/10.1074/mcp.M113.035600
Geng, H. H., Li, R., Su, Y. M., Xiao, J., Pan, M., Cai, X. X., & Ji, X. P. (2016). The circular RNA Cdr1as promotes myocardial infarction by mediating the regulation of miR-7a on its target genes expression. PLoS ONE, 11, e0151753. https://doi.org/10.1371/journal.pone.0151753
Spitz, F., & Furlong, E. E. (2012). Transcription factors: From enhancer binding to developmental control. Nature Reviews Genetics, 13, 613–626. https://doi.org/10.1038/nrg3207
Bulger, M., & Groudine, M. (2011). Functional and mechanistic diversity of distal transcription enhancers. Cell, 144, 327–339. https://doi.org/10.1016/j.cell.2011.01.024
Pott, S., & Lieb, J. D. (2015). What are super-enhancers? Nature genetics, 47, 8–12. https://doi.org/10.1038/ng.3167
Lee, Y., Shioi, T., Kasahara, H., Jobe, S. M., Wiese, R. J., Markham, B. E., & Izumo, S. (1998). The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Molecular and cellular biology, 18, 3120–3129. https://doi.org/10.1128/mcb.18.6.3120
Chandrasekaran, S., Peterson, R. E., Mani, S. K., Addy, B., Buchholz, A. L., Xu, L., Thiyagarajan, T., Kasiganesan, H., Kern, C. B., & Menick, D. R. (2009). Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes. FASEB journal : Official publication of the Federation of American Societies for Experimental Biology, 23, 3851–3864. https://doi.org/10.1096/fj.09-132415
Harris, L. G., Wang, S. H., Mani, S. K., Kasiganesan, H., Chou, C. J., & Menick, D. R. (2016). Evidence for a non-canonical role of HDAC5 in regulation of the cardiac Ncx1 and Bnp genes. Nucleic acids research, 44, 3610–3617. https://doi.org/10.1093/nar/gkv1496
Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-Andre, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013). Super-enhancers in the control of cell identity and disease. Cell, 155, 934–947. https://doi.org/10.1016/j.cell.2013.09.053
Khan, A., & Zhang, X. (2016). dbSUPER: A database of super-enhancers in mouse and human genome. Nucleic acids research, 44, D164-171. https://doi.org/10.1093/nar/gkv1002
Huang, S., Li, X., Zheng, H., Si, X., Li, B., Wei, G., Li, C., Chen, Y., Chen, Y., Liao, W., & Liao Y,&Bin J, . (2019). Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation, 139, 2857–2876. https://doi.org/10.1161/CIRCULATIONAHA.118.038361
Zhang, X., Wang, H., Zhang, Y., Lu, X., Chen, L., & Yang, L. (2014). Complementary sequence-mediated exon circularization. Cell, 159, 134–147. https://doi.org/10.1016/j.cell.2014.09.001
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). The RNA binding protein quaking regulates formation of circRNAs. Cell, 160, 1125–1134. https://doi.org/10.1016/j.cell.2015.02.014
Khan, M. A., Reckman, Y. J., Aufiero, S., van den Hoogenhof, M. M., van der Made, I., Beqqali, A., Koolbergen, D. R., Rasmussen, T. B., van der Velden, J., Creemers, E. E., & Pinto, Y. M. (2016). RBM20 regulates circular RNA production from the titin gene. Circulation research, 119, 996–1003. https://doi.org/10.1161/CIRCRESAHA.116.309568
Paz, I., Kosti, I., Ares, M., Jr., Cline, M., & Mandel-Gutfreund, Y. (2014). RBPmap: A web server for mapping binding sites of RNA-binding proteins. Nucleic acids research, 42, W361-367. https://doi.org/10.1093/nar/gku406
Kafasla, P., Lin, H., Curry, S., & Jackson, R. J. (2011). Activation of picornaviral IRESs by PTB shows differential dependence on each PTB RNA-binding domain. RNA, 17, 1120–1131. https://doi.org/10.1261/rna.2549411
Li, H., Shen, S., Ruan, X., Liu, X., Zheng, J., Liu, Y., Yang, C., Wang, D., Liu, L., Ma, J., Ma, T., Wang, P., Cai, H., Li, Z., Zhao, L., & Xue, Y. (2019). Biosynthetic CircRNA_001160 induced by PTBP1 regulates the permeability of BTB via the CircRNA_001160/miR-195-5p/ETV1 axis. Cell Death & Disease, 10, 960. https://doi.org/10.1038/s41419-019-2191-z
Warf, M. B., Diegel, J. V., von Hippel, P. H., & Berglund, J. A. (2009). The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proc Natl Acad Sci U S A, 106, 9203–9208. https://doi.org/10.1073/pnas.0900342106
Kalsotra, A., Xiao, X., Ward, A. J., Castle, J. C., Johnson, J. M., Burge, C. B., & Cooper, T. A. (2008). A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci U S A, 105, 20333–20338. https://doi.org/10.1073/pnas.0809045105
Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S. (2014). circRNA biogenesis competes with pre-mRNA splicing. Molecular Cell, 56, 55–66. https://doi.org/10.1016/j.molcel.2014.08.019
Kramer, M. C., Liang, D., Tatomer, D. C., Gold, B., March, Z. M., Cherry, S., & Wilusz, J. E. (2015). Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes & Development, 29, 2168–2182. https://doi.org/10.1101/gad.270421.115
Ammar S. Naqvi, Mukta Asnani, Kathryn L. Black, Katharina E. Hayer, Deanne Taylor, Andrei Thomas-Tikhonenko. The role of SRSF3 splicing factor in generating circular RNAs. 2019. BioRxiv.
Li, M., Ding, W., Sun, T., Tariq, M. A., Xu, T., Li, P., & Wang, J. (2018). Biogenesis of circular RNAs and their roles in cardiovascular development and pathology. The FEBS journal, 285, 220–232. https://doi.org/10.1111/febs.14191
Chen, J. F., Mandel, E. M., Thomson, J. M., Wu, Q., Callis, T. E., Hammond, S. M., Conlon, F. L., & Wang, D. Z. (2006). The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature genetics, 38, 228–233. https://doi.org/10.1038/ng1725
Liu, N., Bezprozvannaya, S., Williams, A. H., Qi, X., Richardson, J. A., Bassel-Duby, R., & Olson, E. N. (2008). microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes & Development, 22, 3242–3254. https://doi.org/10.1101/gad.1738708
Izarra, A., Moscoso, I., Canon, S., Carreiro, C., Fondevila, D., Martin-Caballero, J., Blanca, V., Valiente, I., Diez-Juan, A., & Bernad, A. (2017). miRNA-1 and miRNA-133a are involved in early commitment of pluripotent stem cells and demonstrate antagonistic roles in the regulation of cardiac differentiation. Journal of Tissue Engineering and Regenerative Medicine, 11, 787–799. https://doi.org/10.1002/term.1977
Meder, B., Katus, H. A., & Rottbauer, W. (2008). Right into the heart of microRNA-133a. Genes & Development, 22, 3227–3231. https://doi.org/10.1101/gad.1753508
Care, A., Catalucci, D., Felicetti, F., Bonci, D., Addario, A., Gallo, P., Bang, M. L., Segnalini, P., Gu, Y., Dalton, N. D., Elia, L., Latronico, M. V., Hoydal, M., Autore, C., Russo, M. A., Dorn, G. W., 2nd., Ellingsen, O., Ruiz-Lozano, P., Peterson, K. L., … Condorelli, G. (2007). MicroRNA-133 controls cardiac hypertrophy. Nature Medicine, 13, 613–618. https://doi.org/10.1038/nm1582
Valsecchi, V., Pignataro, G., Del Prete, A., Sirabella, R., Matrone, C., Boscia, F., Scorziello, A., Sisalli, M. J., Esposito, E., Zambrano, N., Di Renzo, G., & Annunziato, L. (2011). NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning. Stroke, 42, 754–763. https://doi.org/10.1161/strokeaha.110.597583
Formisano, L., Guida, N., Valsecchi, V., Cantile, M., Cuomo, O., Vinciguerra, A., Laudati, G., Pignataro, G., Sirabella, R., Di Renzo, G., & Annunziato, L. (2015). Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by epigenetic mechanism. Journal of Neuroscience, 35, 7332–7348. https://doi.org/10.1523/JNEUROSCI.2174-14.2015
Kent, R. L., Rozich, J. D., McCollam, P. L., McDermott, D. E., Thacker, U. F., Menick, D. R., McDermott, P. J., & Gt, C. (1993). Rapid expression of the Na(+)-Ca2+ exchanger in response to cardiac pressure overload. American Journal of Physiology, 265, H1024-1029. https://doi.org/10.1152/ajpheart.1993.265.3.H1024
Muller, J. G., Isomatsu, Y., Koushik, S. V., O’Quinn, M., Xu, L., Kappler, C. S., Hapke, E., Zile, M. R., Conway, S. J., & Menick, D. R. (2002). Cardiac-specific expression and hypertrophic upregulation of the feline Na(+)-Ca(2+) exchanger gene H1-promoter in a transgenic mouse model. Circulation research, 90, 158–164. https://doi.org/10.1161/hh0202.103231
Tian, M., Xue, J., Dai, C., Jiang, E., Zhu, B., & Pang, H. (2021). CircSLC8A1 and circNFIX can be used as auxiliary diagnostic markers for sudden cardiac death caused by acute ischemic heart disease. Science and Reports, 11, 4695. https://doi.org/10.1038/s41598-021-84056-5
Chen, X., Han, P., Zhou, T., Guo, X., Song, X., & Li, Y. (2016). circRNADb: A comprehensive database for human circular RNAs with protein-coding annotations. Science and Reports, 6, 34985. https://doi.org/10.1038/srep34985
Yang, Y., Fan, X., Mao, M., Song, X., Wu, P., Zhang, Y., Jin, Y., Yang, Y., Chen, L. L., Wang, Y., Wong, C. C., Xiao, X., & Wang, Z. (2017). Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Research, 27, 626–641. https://doi.org/10.1038/cr.2017.31
van Heesch, S., Witte, F., Schneider-Lunitz, V., Schulz, J. F., Adami, E., Faber, A. B., Kirchner, M., Maatz, H., Blachut, S., Sandmann, C. L., Kanda, M., Worth, C. L., Schafer, S., Calviello, L., Merriott, R., Patone, G., Hummel, O., Wyler, E., Obermayer, B., … Hubner, N. (2019). The translational landscape of the human heart. Cell, 178(242–260), e229. https://doi.org/10.1016/j.cell.2019.05.010
Craig, R., Cortens, J. P., & Beavis, R. C. (2004). Open source system for analyzing, validating, and storing protein identification data. Journal of Proteome Research, 3, 1234–1242. https://doi.org/10.1021/pr049882h
Kim, M. S., Pinto, S. M., Getnet, D., Nirujogi, R. S., Manda, S. S., Chaerkady, R., Madugundu, A. K., Kelkar, D. S., Isserlin, R., Jain, S., Thomas, J. K., Muthusamy, B., Leal-Rojas, P., Kumar, P., Sahasrabuddhe, N. A., Balakrishnan, L., Advani, J., George, B., Renuse, S., … Pandey, A. (2014). A draft map of the human proteome. Nature, 509, 575–581. https://doi.org/10.1038/nature13302
Huang, W., Ling, Y., Zhang, S., Xia, Q., Cao, R., Fan, X., Fang, Z., & Wang Z,&Zhang G, . (2021). TransCirc: An interactive database for translatable circular RNAs based on multi-omics evidence. Nucleic acids research, 49, D236–D242. https://doi.org/10.1093/nar/gkaa823
Saw PE,&Song EW, . (2020). siRNA therapeutics: A clinical reality. Sci China Life Sci, 63, 485–500. https://doi.org/10.1007/s11427-018-9438-y
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013). Delivery materials for siRNA therapeutics. Nature Materials, 12, 967–977. https://doi.org/10.1038/nmat3765
Hanan, M., Simchovitz, A., Yayon, N., Vaknine, S., Cohen-Fultheim, R., Karmon, M., Madrer, N., Rohrlich, T. M., Maman, M., Bennett, E. R., Greenberg, D. S., Meshorer, E., Levanon, E. Y., Soreq, H., & Kadener, S. (2020). A Parkinson’s disease CircRNAs resource reveals a link between circSLC8A1 and oxidative stress. EMBO Molecular Medecine, 12, e13551. https://doi.org/10.15252/emmm.202013551
Lu, Q., Liu, T., Feng, H., Yang, R., Zhao, X., Chen, W., Jiang, B., Qin, H., Guo, X., Liu, M., Li, L., & Guo, H. (2019). Circular RNA circSLC8A1 acts as a sponge of miR-130b/miR-494 in suppressing bladder cancer progression via regulating PTEN. Molecular Cancer, 18, 111. https://doi.org/10.1186/s12943-019-1040-0
Nguyen, G. N., Everett, J. K., Kafle, S., Roche, A. M., Raymond, H. E., Leiby, J., Wood, C., Assenmacher, C. A., Merricks, E. P., Long, C. T., Kazazian, H. H., Nichols, T. C., Bushman, F. D., & Sabatino, D. E. (2021). A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nature Biotechnology, 39, 47–55. https://doi.org/10.1038/s41587-020-0741-7
Li, Y., Zheng, Q., Bao, C., Li, S., Guo, W., Zhao, J., Chen, D., Gu, J., He, X., & Huang, S. (2015). Circular RNA is enriched and stable in exosomes: A promising biomarker for cancer diagnosis. Cell Research, 25, 981–984. https://doi.org/10.1038/cr.2015.82
Zhao, Z., Li, X., Jian, D., Hao, P., Rao, L., & Li, M. (2017). Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of pre-diabetes and type 2 diabetes mellitus. Acta Diabetologica, 54, 237–245. https://doi.org/10.1007/s00592-016-0943-0
Cui, X., Niu, W., Kong, L., He, M., Jiang, K., Chen, S., Zhong, A., Li, W., Lu, J., & Zhang, L. (2016). hsa_circRNA_103636: Potential novel diagnostic and therapeutic biomarker in Major depressive disorder. Biomarkers in Medicine, 10, 943–952. https://doi.org/10.2217/bmm-2016-0130
Vausort, M., Salgado-Somoza, A., Zhang, L., Leszek, P., Scholz, M., Teren, A., Burkhardt, R., Thiery, J., Wagner, D. R., & Devaux, Y. (2016). Myocardial infarction-associated circular RNA predicting left ventricular dysfunction. Journal of the American College of Cardiology, 68, 1247–1248. https://doi.org/10.1016/j.jacc.2016.06.040
Qi Li, Zhongjie Yu, Mengyang Li et al. The expression profiles and role of circular RNA in peripheral blood of myocardial infarction patients, 09 June 2020, Preprint (Version 1) available at Research Square.
Zhu, Q., Zhang, X., Zai, H. Y., Jiang, W., Zhang, K. J., He, Y. Q., & Hu, Y. (2021). circSLC8A1 sponges miR-671 to regulate breast cancer tumorigenesis via PTEN/PI3k/Akt pathway. Genomics, 113, 398–410. https://doi.org/10.1016/j.ygeno.2020.12.006
Lin, C., Zhong, W., Yan, W., Yang, J., Zheng, W., & Wu, Q. (2020). Circ-SLC8A1 regulates osteoporosis through blocking the inhibitory effect of miR-516b-5p on AKAP2 expression. The Journal of Gene Medicine, 22, e3263. https://doi.org/10.1002/jgm.3263
Wang, D., Yan, S., Wang, L., Li, Y., & Qiao, B. (2021). circSLC8A1 acts as a tumor suppressor in prostate cancer via sponging miR-21. BioMed Research International, 2021, 6614591. https://doi.org/10.1155/2021/6614591
Qiao, L., Hu, S., Liu, S., Zhang, H., Ma, H., Huang, K., Li, Z., Su, T., Vandergriff, A., Tang, J., Allen, T., Dinh, P. U., Cores, J., Yin, Q., Li, Y., & Cheng, K. (2019). microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. The Journal of Clinical Investigation, 129, 2237–2250. https://doi.org/10.1172/JCI123135
Cheng, Y., Zhu, P., Yang, J., Liu, X., Dong, S., Wang, X., Chun, B., Zhuang, J., & Zhang, C. (2010). Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovascular research, 87, 431–439. https://doi.org/10.1093/cvr/cvq082
Wang, X., Zhang, X., Ren, X. P., Chen, J., Liu, H., Yang, J., Medvedovic, M., Hu, Z., & Fan, G. C. (2010). MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury. Circulation, 122, 1308–1318. https://doi.org/10.1161/CIRCULATIONAHA.110.964684
Zhao, D., Shun, E., Ling, F., Liu, Q., Warsi, A., Wang, B., Zhou, Q., Zhu, C., Zheng, H., Liu, K., & Zheng, X. (2020). Plk2 regulated by miR-128 induces ischemia-reperfusion injury in cardiac cells. Molecular therapy. Nucleic acids, 19, 458–467. https://doi.org/10.1016/j.omtn.2019.11.029
Li, H., Zhang, X., Wang, F., Zhou, L., Yin, Z., Fan, J., Nie, X., Wang, P., Fu, X. D., Chen, C., & Wang, D. W. (2016). MicroRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation, 134, 734–751. https://doi.org/10.1161/CIRCULATIONAHA.116.023926
Qi H, Ren J, Ba L, Song C, Zhang Q, Cao Y, Shi P, Fu B, Liu Y, & Sun HJMtNa (2020) MSTN attenuates cardiac hypertrophy through inhibition of excessive cardiac autophagy by blocking AMPK /mTOR and miR-128/PPARγ/NF-κB. 19:507–522. https://doi.org/10.1016/j.omtn.2019.12.003
Tsitsipatis, D., Grammatikakis, I., Driscoll, R. K., Yang, X., Abdelmohsen, K., Harris, S. C., Yang, J. H., Herman, A. B., Chang, M. W., Munk, R., Martindale, J. L., Mazan-Mamczarz, K., De, S., Lal, A., & Gorospe, M. (2021). AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production. Nucleic acids research, 49, 1631–1646. https://doi.org/10.1093/nar/gkaa1246
Abdelmohsen, K., Panda, A. C., Munk, R., Grammatikakis, I., Dudekula, D. B., De, S., Kim, J., Noh, J. H., Kim, K. M., Martindale, J. L., & Gorospe, M. (2017). Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biology, 14, 361–369. https://doi.org/10.1080/15476286.2017.1279788
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This work was supported by the National Natural Science Foundation of China (grant number 81900259) and the Natural Science Foundation of Shandong Province (grant number JQ201815).
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Ding, L., Li, M., Yang, F. et al. CircNCX1: the “Lord of the Ring” in the Heart — Insight into Its Sequence Characteristic, Expression, Molecular Mechanisms, and Clinical Application. J. of Cardiovasc. Trans. Res. 15, 571–586 (2022). https://doi.org/10.1007/s12265-021-10176-y
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DOI: https://doi.org/10.1007/s12265-021-10176-y