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Emerging Role of RNA m5C Modification in Cardiovascular Diseases

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Abstract

Epitranscriptomics is the emerging field of research that comprises the study of epigenetics changes in RNAs. Progressing development in the field of epigenetics has helped to manage and comprehend human diseases. RNA methylation regulates all aspects of RNA functions, which are involved in the pathogenesis of human diseases. Interestingly, RNA m5C methylation is significantly linked to various types of human disease, including cardiovascular diseases (CVD). The m5C methylation is controlled by m5C regulatory proteins, which act as methyltransferase, demethyltransferase, and RNA-binding protein. Dysregulated expression in m5C regulatory proteins is significantly associated with cardiovascular disease, and these regulatory proteins have crucial roles in biological and cellular functions. This review is mainly focused on the role of RNA m5C modification in CVD and mitochondrial dysfunction. Thus, m5C will contribute to discovering the new diagnostic marker and therapeutic target for CVD.

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Abbreviations

Asp:

Asparagine

Aza-IP:

5-Azacytidine-mediated RNA immunoprecipitation

CLIP:

Cross-linking and immunoprecipitation

CVD:

Cardiovascular disease

DNMT2:

DNA methyltransferase 2

DS:

Dubowitz syndrome

Gly:

Glycine

Leu:

Leucine

lncRNA:

Long noncoding RNA

m5C:

5-Methylcytosine

m5C-RIP:

5-Methylcytosine-RNA immunoprecipitation

m6A:

N6-Methyladenosine

Me-RIP:

Methylated RNA immunoprecipitation

Met:

Methionine

miRNA:

Micro RNA

mRNA:

Messenger RNA

mt-tRNA:

Mitochondrial transfer RNA

RNMT:

RNA methyl transferase

rRNA:

Ribosomal RNA

SAM:

S-Adenosyl-L-methionine

TAWO-seq:

TET-assisted WO-seq

TCGA:

The Cancer Genome Atlas

TET family:

Ten-eleven translocation methylcytosine dioxygenases

TNF-α:

Tumor necrosis factor-α

TRDMT1:

TRNA aspartic acid methyltransferase 1

tRNA:

Transfer RNA

UTR:

Untranslated region

Val:

Valine

WHO:

World Health Organization

References

  1. Anonymous, The top 10 causes of death by WHO, 2020. Retrieved from; https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.

  2. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33:245–54.

    Article  CAS  PubMed  Google Scholar 

  3. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jones P, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–41.

    Article  CAS  PubMed  Google Scholar 

  5. Stellos K. The rise of epitranscriptomic era: implications for cardiovascular disease. Cardiovasc Res. 2017;113:e2–3.

    Article  CAS  PubMed  Google Scholar 

  6. Cohn WE. Pseudouridine, a carbon-carbon linked ribonucleoside in ribonucleic acids: isolation, structure, and chemical characteristics. J Biol Chem. 2017;235:1488–98.

    Article  Google Scholar 

  7. Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, et al. MODOMICS: a database of RNA modification pathways. Nucleic Acids Res. 2018;46:303–7.

    Article  Google Scholar 

  8. Korlach J, Turner SW. Going beyond five bases in DNA sequencing. Curr Opin Struct Biol. 2012;22:251–61.

    Article  CAS  PubMed  Google Scholar 

  9. Dubin DT, Taylor RH. The methylation state of poly A-containing messenger RNA from cultured hamster cells. Nucleic Acids Res. 1975;2:1653–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Trixl L, Lusser A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA. 2019;10:e1510.

    Article  PubMed  Google Scholar 

  11. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–76.

    Article  CAS  PubMed  Google Scholar 

  12. Amort T, Rieder D, Wille A, Khokhlova-Cubberley D, Riml C, Trixl L, Lusser A. Distinct 5-methylcytosine profiles in poly(A) RNA from mouse embryonic stem cells and brain. Genome Biol. 2017;18(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Squires JE, Patel HR, Nousch M, Sibbritt T, Humphreys DT, Parker BJ, Preiss T. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 2012;40:5023–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Motorin Y, Lyko F, Helm M. 5-methylcytosine in RNA: detection, enzymatic formation, and biological functions. Nucleic acids Res. 2010;38:1415–30.

    Article  CAS  PubMed  Google Scholar 

  15. Brown DA, Perry JB, Allen ME, et al. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017;14(4):238–50.

    Article  CAS  PubMed  Google Scholar 

  16. Schaefer M, Pollex T, Hanna K, Tuorto F, Meusburger M, Helm M, Lyko F. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 2010;24:1590–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bohnsack KE, Höbartner C, Bohnsack MT. Eukaryotic 5-methylcytosine (m5C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes (Basel). 2019;10(2):102.

    Article  CAS  PubMed  Google Scholar 

  18. Motorin Y, Lyko F, Helm M. 5-methylcytosine in RNA: detection, enzymatic formation, and biological functions. Nucleic acids Res. 2010;38(5):1415–30.

    Article  CAS  PubMed  Google Scholar 

  19. Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, et al. Methylation of tRNA Asp by the DNA methyltransferase homolog Dnmt2. Science. 2006;311:395–8.

    Article  CAS  PubMed  Google Scholar 

  20. Reid R, Greene PJ, Santi DV. Exposition of a family of RNA m5C methyltransferases from searching genomic and proteomic sequences. Nucleic Acids Res. 1999;27:3138–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Metodiev MD, Spåhr H, Loguercio Polosa P, Meharg C, Becker C, Altmueller J, Habermann B, Larsson NG, Ruzzenente B. NSUN4 is a dual function mitochondrial protein required for both methylation of 12S rRNA and coordination of mitoribosomal assembly. PLoS Genet. 2014;10:e1004110.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Van Haute L, Lee SY, McCann BJ, Powell CA, Bansal D, Vasiliauskaitė L, Garone C, Shin S, Kim JS, Frye M, Gleeson JG, Miska EA, Rhee HW, Minczuk M. NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs. Nucleic Acids Res. 2019;47(16):8720–33.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sun Z, Xue S, Xu H, Hu X, Chen S, Yang Z, Yang Y, Ouyang J, Cui H. Effects of NSUN2 deficiency on the mRNA 5-methylcytosine modification and gene expression profile in HEK293 cells. Epigenomics. 2019;11:439–53.

    Article  CAS  PubMed  Google Scholar 

  24. Li Y, Li J, Luo M, Zhou C, Shi X, Yang W, Lu Z, Chen Z, Sun N, He J. Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma. Cancer Lett. 2018;430:57–66.

    Article  CAS  PubMed  Google Scholar 

  25. Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, Li A, Wang X, Bhattarai DP, Xiao W, et al. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res. 2017;27:606–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brzezicha B, Schmidt M, Makalowska I, Jarmolowski A, Pienkowska J, Szweykowska-Kulinska Z. Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the pre-tRNA Leu (CAA). Nucleic Acids Res. 2006;34:6034–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S, Kellner S, Frye M, Helm M, Stoecklin G, Lyko F. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol. 2012;19:900–5.

    Article  CAS  PubMed  Google Scholar 

  28. Xue S, Xu H, Sun Z, Shen H, Chen S, Ouyang J, Zhou Q, Hu X, Cui H. Depletion of TRDMT1 affects 5-methylcytosine modification of mRNA and inhibits HEK293 cell proliferation and migration. Biochem Biophys Res Commun. 2019;520:60–6.

    Article  CAS  PubMed  Google Scholar 

  29. Chen YS, Yang WL, Zhao YL, Yang YG. Dynamic transcriptomic m5 C and its regulatory role in RNA processing. Wiley Interdiscip Rev RNA. 2021;12(4):e1639.

  30. Li X, Meng Y. Expression and prognostic characteristics of m5 C regulators in low-grade glioma. J Cell Mol Med. 2021;25(3):1383–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Helm M. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34:721–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Strobel MC, Abelson J. Effect of intron mutations on processing and function of Saccharomyces cerevisiae SUP53 tRNA in vitro and in vivo. Mol Cell Biol. 1986;6:2663–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schosserer M, Minois N, Angerer TB, Amring M, Dellago H, Harreither E, Calle-Perez A, Pircher A, Gerstl MP, Pfeifenberger S, et al. Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan. Nat Commun. 2015;6:6158.

    Article  CAS  PubMed  Google Scholar 

  34. Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, Liu KF. TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J Biol Chem. 2021;296:100087.

    Article  CAS  PubMed  Google Scholar 

  35. Chistiakov DA, Shkurat TP, Melnichenko AA, Grechko AV, Orekhov AN. The role of mitochondrial dysfunction in cardiovascular disease: a brief review. Ann Med. 2018;50(2):121–7.

    Article  CAS  PubMed  Google Scholar 

  36. Lin H, Miyauchi K, Harada T, Okita R, Takeshita E, Komaki H, Fujioka K, Yagasaki H, Goto YI, Yanaka K, et al. CO2-sensitive tRNA modification associated with human mitochondrial disease. Nat Commun. 2018;9:1875.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Suzuki T, Nagao A, Suzuki T. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet. 2011;45:299–329.

    Article  CAS  PubMed  Google Scholar 

  38. Trixl L, Amort T, Wille A, Zinni M, Ebner S, Hechenberger C, Lusser A. RNA cytosine methyltransferase Nsun3 regulates embryonic stem cell differentiation by promoting mitochondrial activity. Cell Mol Life Sci. 2018;75(8):1483–97.

    Article  CAS  PubMed  Google Scholar 

  39. Spåhr H, Habermann B, Gustafsson CM, Larsson NG, Hallberg BM. Structure of the human MTERF4–NSUN4 protein complex that regulates mitochondrial ribosome biogenesis. Proc Natl Acad Sci USA. 2012;109:15253–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Huang T, Chen W, Liu J, Gu N, Zhang R. Genome-wide identification of mRNA 5-methylcytosine in mammals. Nat Struct Mol Biol. 2019;26(5):380–8.

    Article  CAS  PubMed  Google Scholar 

  41. Kawarada L, Suzuki T, Ohira T, Hirata S, Miyauchi K, Suzuki T. ALKBH1 is an RNA dioxygenase responsible for cytoplasmic and mitochondrial tRNA modifications. Nucleic Acids Res. 2017;45(12):7401–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang B, Jiang H, Dong Z, Sun A, Ge J. The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases. Genes Dis. 2020;8(6):746–58.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lewinska A, Wnuk M, Grabowska W, Zabek T, Semik E, Sikora E, Bielak-Zmijewska A. Curcumin induces oxidation-dependent cell cycle arrest mediated by SIRT7 inhibition of rDNA transcription in human aortic smooth muscle cells. Toxicol Lett. 2015;233:227–38.

    Article  CAS  PubMed  Google Scholar 

  44. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, He C. N6-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ghanbarian H, Wagner N, Polo B, Baudouy D, Kiani J, Michiels JF, Wagner KD. Dnmt2/Trdmt1 as mediator of RNA polymerase II transcriptional activity in cardiac growth. PLoS ONE. 2016;11(6):e0156953.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cheng JX, Chen L, Li Y, Cloe A, Yue M, Wei J, Vardiman JW. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat Commun. 2018;9(1):1163.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Luo Y, Feng J, Xu Q, Wang W, Wang X. NSun2 deficiency protects endothelium from inflammation via mRNA methylation of ICAM-1. Circ Res. 2016;118(6):944–56.

    Article  CAS  PubMed  Google Scholar 

  48. Yuan S, Tang H, Xing J, et al. Methylation by NSun2 represses the levels and function of microRNA 125b. Mol Cell Biol. 2014;34(19):3630–41.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Yin L, Zhu X, Novák P, Zhou L, Gao L, Yang M, Zhao G, Yin K. The epitranscriptome of long noncoding RNAs in metabolic diseases. Clin Chim Acta. 2021;515:80–9.

    Article  CAS  PubMed  Google Scholar 

  50. Martens MA, Wilson SJ, Reutens DC. Williams syndrome: a critical review of the cognitive, behavioral and neuroanatomical phenotype. J Child Psychol Psychiatry. 2008;14:576–608.

    Article  Google Scholar 

  51. Wang N, Tang H, Wang X, Wang W, Feng J. Homocysteine upregulates interleukin-17A expression via NSun2-mediated RNA methylation in T lymphocytes. Biochem Biophys Res Commun. 2017;493(1):94–9. https://doi.org/10.1016/j.bbrc.2017.09.069.

    Article  CAS  PubMed  Google Scholar 

  52. He Y, Zhang H, Yin F, et al. Novel insights into the role of 5-methylcytosine RNA methylation in human abdominal aortic aneurysm. Front Biosci (Landmark Ed). 2021;26(11):1147–65. https://doi.org/10.52586/5016.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the contribution of Dr. Anitha Roy, who was involved in the editing and formatting of the manuscript.

Funding

This work was supported by the Science and Engineering Research Board (SERB), Government of India (EEQ/2019/000411).

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Authors and Affiliations

  1. Centre for Cellular and Molecular Research, Saveetha Dental College & Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India

    Kannan Balachander, Jayaseelan Vijayashree Priyadharsini & Arumugam Paramasivam

  2. Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India

    Anitha Roy

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  1. Kannan Balachander
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  2. Jayaseelan Vijayashree Priyadharsini
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Contributions

K. Balachander undertook literature mining from various reputed databases, drafted the manuscript, and prepared illustrations. Dr. A. Paramasivam and Dr. J. Vijayashree Priyadharsini gave the concept for this article and are responsible for manuscript proofreading and validating the entire manuscript.

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Correspondence to Arumugam Paramasivam.

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Balachander, K., Priyadharsini, J.V., Roy, A. et al. Emerging Role of RNA m5C Modification in Cardiovascular Diseases. J. of Cardiovasc. Trans. Res. 16, 598–605 (2023). https://doi.org/10.1007/s12265-022-10336-8

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