The Role of MA and MAm RNA Modifications in the Pathogenesis of Diabetes Mellitus

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2023 Jul 24

PMID 37484960

Authors

Daniel Benak

Stepanka Benakova

Lydie Plecita-Hlavata

Marketa Hlavackova

Affiliations

Soon will be listed here.

Abstract

The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of mA and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about mA and mAm modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.

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References

Wang X, Lu Z, Gomez A, Hon G, Yue Y, Han D . N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2013; 505(7481):117-20. PMC: 3877715. DOI: 10.1038/nature12730. View

Zhang Q, Xiong L, Wei T, Liu Q, Yan L, Chen J . Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma. Oncogene. 2023; 42(19):1509-1523. DOI: 10.1038/s41388-023-02665-y. View

Hsiao Y, Shen F, Weng S, Wang P, Chen Y, Lee J . Multiple Single Nucleotide Polymorphism Testing Improves the Prediction of Diabetic Retinopathy Risk with Type 2 Diabetes Mellitus. J Pers Med. 2021; 11(8). PMC: 8398882. DOI: 10.3390/jpm11080689. View

Hsu P, Zhu Y, Ma H, Guo Y, Shi X, Liu Y . Ythdc2 is an N-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017; 27(9):1115-1127. PMC: 5587856. DOI: 10.1038/cr.2017.99. View

De Jesus D, Zhang Z, Kahraman S, Brown N, Chen M, Hu J . mA mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes. Nat Metab. 2019; 1(8):765-774. PMC: 6924515. DOI: 10.1038/s42255-019-0089-9. View

Yang K, Sun J, Zhang Z, Xiao M, Ren D, Liu S . Reduction of mRNA mA associates with glucose metabolism via YTHDC1 in human and mice. Diabetes Res Clin Pract. 2023; 198:110607. DOI: 10.1016/j.diabres.2023.110607. View

Marselli L, Thorne J, Dahiya S, Sgroi D, Sharma A, Bonner-Weir S . Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010; 5(7):e11499. PMC: 2903480. DOI: 10.1371/journal.pone.0011499. View

Lee Y, Choe J, Park O, Kim Y . Molecular Mechanisms Driving mRNA Degradation by mA Modification. Trends Genet. 2020; 36(3):177-188. DOI: 10.1016/j.tig.2019.12.007. View

Li X, Jiang Y, Sun X, Wu Y, Chen Z . METTL3 is required for maintaining β-cell function. Metabolism. 2021; 116:154702. DOI: 10.1016/j.metabol.2021.154702. View

10.

Mauer J, Jaffrey S . FTO, m A , and the hypothesis of reversible epitranscriptomic mRNA modifications. FEBS Lett. 2018; 592(12):2012-2022. DOI: 10.1002/1873-3468.13092. View

11.

Goh Y, Koh C, Sim D, Roca X, Goh W . METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing. Nucleic Acids Res. 2020; 48(16):9250-9261. PMC: 7498333. DOI: 10.1093/nar/gkaa684. View

12.

Wang P, Doxtader K, Nam Y . Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol Cell. 2016; 63(2):306-317. PMC: 4958592. DOI: 10.1016/j.molcel.2016.05.041. View

13.

Hubacek J, Sedova L, Olisarova V, Adamkova V, Tothova V . Different prevalence of T2DM risk alleles in Roma population in comparison with the majority Czech population. Mol Genet Genomic Med. 2020; 8(9):e1361. PMC: 7507457. DOI: 10.1002/mgg3.1361. View

14.

Sun H, Zhang M, Li K, Bai D, Yi C . Cap-specific, terminal N-methylation by a mammalian mAm methyltransferase. Cell Res. 2018; 29(1):80-82. PMC: 6318281. DOI: 10.1038/s41422-018-0117-4. View

15.

Wan S, Hua Q, Xing Y, Cheng Y, Zhou S, Sun Y . Decreased Urine N6-methyladenosine level is closely associated with the presence of diabetic nephropathy in type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2022; 13:986419. PMC: 9553099. DOI: 10.3389/fendo.2022.986419. View

16.

Semenovykh D, Benak D, Holzerova K, Cerna B, Telensky P, Vavrikova T . Myocardial m6A regulators in postnatal development: effect of sex. Physiol Res. 2022; 71(6):877-882. PMC: 9814979. View

17.

Li X, Yang Y, Chen Z . Downregulation of the mA reader protein YTHDC1 leads to islet β-cell failure and diabetes. Metabolism. 2022; 138:155339. DOI: 10.1016/j.metabol.2022.155339. View

18.

Sun Q, Geng H, Zhao M, Li Y, Chen X, Sha Q . FTO-mediated m A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease. Clin Transl Med. 2022; 12(6):e942. PMC: 9217105. DOI: 10.1002/ctm2.942. View

19.

Shen F, Huang W, Huang J, Xiong J, Yang Y, Wu K . Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab. 2014; 100(1):E148-54. PMC: 5399497. DOI: 10.1210/jc.2014-1893. View

20.

De Jesus D, Kulkarni R . Epigenetic modifiers of islet function and mass. Trends Endocrinol Metab. 2014; 25(12):628-36. DOI: 10.1016/j.tem.2014.08.006. View