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CircNCX1: the “Lord of the Ring” in the Heart — Insight into Its Sequence Characteristic, Expression, Molecular Mechanisms, and Clinical Application

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A Correction to this article was published on 22 November 2021

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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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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

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  Google Scholar 

  16. 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

    Article  CAS  Google Scholar 

  17. 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

    Article  CAS  Google Scholar 

  18. 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

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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

  20. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  Google Scholar 

  33. 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

    Article  CAS  Google Scholar 

  34. 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

    Article  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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

  39. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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

    Article  CAS  PubMed  Google Scholar 

  41. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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

    Article  CAS  PubMed  Google Scholar 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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

    Article  CAS  PubMed  Google Scholar 

  49. 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

    Article  CAS  PubMed  Google Scholar 

  50. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pott, S., & Lieb, J. D. (2015). What are super-enhancers? Nature genetics, 47, 8–12. https://doi.org/10.1038/ng.3167

    Article  CAS  PubMed  Google Scholar 

  54. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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

    Article  CAS  Google Scholar 

  56. 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

    Article  CAS  PubMed  Google Scholar 

  57. 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

    Article  CAS  PubMed  Google Scholar 

  58. 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

    Article  CAS  PubMed  Google Scholar 

  59. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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

    Article  CAS  PubMed  Google Scholar 

  61. 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

    Article  CAS  PubMed  Google Scholar 

  62. 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

    Article  CAS  PubMed  Google Scholar 

  63. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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

    Article  CAS  Google Scholar 

  66. 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

    Article  PubMed  PubMed Central  Google Scholar 

  67. 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

    Article  PubMed  PubMed Central  Google Scholar 

  68. 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

    Article  CAS  PubMed  Google Scholar 

  69. 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

    Article  CAS  Google Scholar 

  70. 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.

  71. 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

    Article  CAS  PubMed  Google Scholar 

  72. 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

    Article  CAS  PubMed  Google Scholar 

  73. 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

    Article  CAS  Google Scholar 

  74. 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

    Article  CAS  PubMed  Google Scholar 

  75. 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

    Article  CAS  Google Scholar 

  76. 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

    Article  CAS  PubMed  Google Scholar 

  77. 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

    Article  CAS  PubMed  Google Scholar 

  78. 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

    Article  CAS  PubMed  Google Scholar 

  79. 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

    Article  CAS  PubMed  Google Scholar 

  80. 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

    Article  CAS  PubMed  Google Scholar 

  81. 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

    Article  CAS  Google Scholar 

  82. 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

    Article  CAS  Google Scholar 

  83. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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

    Article  CAS  Google Scholar 

  85. 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

    Article  CAS  PubMed  Google Scholar 

  86. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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

    Article  CAS  PubMed  Google Scholar 

  88. 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

    Article  CAS  Google Scholar 

  89. 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

    Article  CAS  PubMed  Google Scholar 

  90. 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

    Article  CAS  Google Scholar 

  91. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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

    Article  CAS  PubMed  Google Scholar 

  93. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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

    Article  CAS  PubMed  Google Scholar 

  95. 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

    Article  CAS  PubMed  Google Scholar 

  96. 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

    Article  PubMed  Google Scholar 

  97. 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.

  98. 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

    Article  CAS  PubMed  Google Scholar 

  99. 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

    Article  CAS  PubMed  Google Scholar 

  100. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 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

    Article  PubMed  PubMed Central  Google Scholar 

  102. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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

    Article  PubMed  PubMed Central  Google Scholar 

  104. 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

    Article  CAS  PubMed  Google Scholar 

  105. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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

  107. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

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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  1. School of Basic Medical Sciences, Qingdao University, Qingdao, 266071, China

    Lin Ding, Mengyang Li, Fuqing Yang & Jianxun Wang

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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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