Abstract
As the most prevalent and abundant transcriptional modification in the eukaryotic genome, the continuous and dynamic regulation of N6-methyladenosine (m6A) has been shown to play a vital role in physiological and pathological processes of cardiovascular diseases (CVDs), such as ischemic heart failure (HF), myocardial hypertrophy, myocardial infarction (MI), and cardiomyogenesis. Regulation is achieved by modulating the expression of m6A enzymes and their downstream cardiac genes. In addition, this process has a major impact on different aspects of internal biological metabolism and several other external environmental effects associated with the development of CVDs. However, the exact molecular mechanism of m6A epigenetic regulation has not been fully elucidated. In this review, we outline recent advances and discuss potential therapeutic strategies for managing m6A in relation to several common CVD-related metabolic disorders and external environmental factors. Note that an appropriate understanding of the biological function of m6A in the cardiovascular system will pave the way towards exploring the mechanisms responsible for the development of other CVDs and their associated symptoms. Finally, it can provide new insights for the development of novel therapeutic agents for use in clinical practice.
概 要
作为真核生物基因组中最普遍和最丰富的转录修饰, N6-甲基腺苷(m6A)持续而动态性的调节在缺血性心力衰竭、 心肌肥大和心肌梗死等心血管系统疾病的生理和病理过程中发挥着重要作用. 此外, m6A RNA 甲基化通过改变多种 m6A 酶及下游靶基因的表达, 对与心血管系统疾病发生发展相关的内在生物代谢和外在环境因素起着重要的调节作用. 但是, 目前仍不清楚 m6A 表观遗传调节具体的分子生物学机制. 在此, 我们概述了 m6A RNA 甲基化最新的研究进展及其在常见心血管系统疾病和心血管相关代谢紊乱病理发展中的作用.这将有助于我们正确了解 m6A 在心血管系统中的生物学作用, 并为进一步探索心血管疾病及其相关临床症状的发生机制和开发临床治疗药物, 提供新的理论依据和思路.
Similar content being viewed by others
References
Abdul-Ghani MA, Jayyousi A, Defronzo RA, et al., 2019. Insulin resistance the link between T2DM and CVD: basic mechanisms and clinical implications. Curr Vasc Pharmacol, 17(2):153–163. https://doi.org/10.2174/1570161115666171010115119
Asher G, Gatfield D, Stratmann M, et al., 2008. Sirt1 regulates circadian clock gene expression through PER2 deacetylation. Cell, 134(2):317–328. https://doi.org/10.1016/j.cell.2008.06.050
Bartosovic M, Molares HC, Gregorova P, et al., 2017. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing. Nucleic Acids Res, 45(19):11356–11370. https://doi.org/10.1093/nar/gkx778
Bayarsaihan D, 2011. Epigenetic mechanisms in inflammation. J Dent Res, 90(1):9–17. https://doi.org/10.1177/0022034510378683
Bochmann L, Sarathchandra P, Mori F, et al., 2010. Revealing new mouse epicardial cell markers through transcriptomics. PLoS ONE, 5(6):e11429. https://doi.org/10.1371/journal.pone.0011429
Boissel S, Reish O, Proulx K, et al., 2009. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet, 85(1):106–111. https://doi.org/10.1016/j.ajhg.2009.06.002
Buysschaert I, Schmidt T, Roncal C, et al., 2008. Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis. J Cell Mol Med, 12(6b):2533–2551. https://doi.org/10.1111/j.1582-4934.2008.00515.x
Cai CL, Martin JC, Sun YF, et al., 2008. A myocardial lineage derives from Tbx18 epicardial cells. Nature, 454(7200):104–108. https://doi.org/10.1038/nature06969
Cai M, Liu Q, Jiang Q, et al., 2019. Loss of m6A on FAM134B promotes adipogenesis in porcine adipocytes through m6A-YTHDF2-dependent way. IUBMB Life, 71(5):580–586. https://doi.org/10.1002/iub.1974
Calvanese V, Fraga MF, 2012. Epigenetics of embryonic stem cells. Adv Exp Med Biol, 741:231–253. https://doi.org/10.1007/978-1-4614-2098-9_16
Carnevali L, Graiani G, Rossi S, et al., 2014. Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice. PLoS ONE, 9(4):e95499. https://doi.org/10.1371/journal.pone.0095499
Cecil JE, Tavendale R, Watt P, et al., 2008. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med, 359(24):2558–2566. https://doi.org/10.1056/NEJMoa0803839
Chen JL, Du B, 2019. Novel positioning from obesity to cancer: FTO, an m6A RNA demethylase, regulates tumour progression. J Cancer Res Clin Oncol, 145(1):19–29. https://doi.org/10.1007/s00432-018-2796-0
Cheng H, Xuan HW, Green CD, et al., 2018. Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci USA, 115(29):7611–7616. https://doi.org/10.1073/pnas.1800656115
Church C, Moir L, McMurray F, et al., 2010. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet, 42(12):1086–1092. https://doi.org/10.1038/ng.713
Cole MA, Jamil AHA, Heather LC, et al., 2016. On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury. FASEB J, 30(8):2684–2697. https://doi.org/10.1096/fj.201500094R
Cosselman KE, Navas-Acien A, Kaufman JD, 2015. Environmental factors in cardiovascular disease. Nat Rev Cardiol, 12(11):627–642. https://doi.org/10.1038/nrcardio.2015.152
da Luz Sousa Fialho M, Jamil AHA, Stannard GA, et al., 2019. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease. Biochim Biophys Acta Mol Basis Dis, 1865(4):831–843. https://doi.org/10.1016/j.bbadis.2018.09.024
Dang CV, Semenza GL, 1999. Oncogenic alterations of metabolism. Trends Biochem Sci, 24(2):68–72.
Daoud H, Zhang D, McMurray F, et al., 2016. Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay. J Med Genet, 53(3):200–207. https://doi.org/10.1136/jmedgenet-2015-103399
Daya M, Pujianto DA, Witjaksono F, et al., 2019. Obesity risk and preference for high dietary fat intake are determined by FTO rs9939609 gene polymorphism in selected Indonesian adults. Asia Pac J Clin Nutr, 28(1):183–191. https://doi.org/10.6133/apjcn.201903_28(1).0024
Dina C, Meyre D, Gallina S, et al., 2007. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet, 39(6):724–726. https://doi.org/10.1038/ng2048
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al., 2012. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature, 485(7397):201–206. https://doi.org/10.1038/nature11112
Dorn LE, Lasman L, Chen J, et al., 2019. The N6-methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation, 139(4): 533–545. https://doi.org/10.1161/circulationaha.118.036146
el Azzouzi H, Leptidis S, Dirkx E, et al., 2013. The hypoxia-inducible microRNA cluster miR-199a-214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab, 18(3):341–354. https://doi.org/10.1016/j.cmet2013.08.009
Essop MF, 2007. Cardiac metabolic adaptations in response to chronic hypoxia. J Physiol, 584(3):715–726. https://doi.org/10.1113/jphysiol.2007.143511
Fedeles BI, Singh V, Delaney JC, et al., 2015. The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J Biol Chem, 290(34):20734–20742. https://doi.org/10.1074/jbc.R115.656462
Feng ZH, Li QM, Meng RS, et al., 2018. METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells. J Cell Mol Med, 22(5):2558–2568. https://doi.org/10.1111/jcmm.13491
Fernández-Morera JL, Calvanese V, Rodríguez-Rodero S, et al., 2010. Epigenetic regulation of the immune system in health and disease. Tissue Antigens, 76(6):431–439. https://doi.org/10.1111/j.1399-0039.2010.01587.x
Fiechter M, Haider A, Bengs S, et al., 2019. Sex differences in the association between inflammation and ischemic heart disease. Thromb Haemost, 119(9):1471–1480. https://doi.org/10.1055/s-0039-1692442
Fu Y, Dominissini D, Rechavi G, et al., 2014. Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet, 15(5):293–306. https://doi.org/10.1038/nrg3724
Fustin JM, Doi M, Yamaguchi Y, et al., 2013. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155(4):793–806. https://doi.org/10.1016/j.cell.2013.10.026
Gan HL, Hong L, Yang FL, et al., 2019. Progress in epigenetic modification of mRNA and the function of m6A modification. Chin J Biotechnol, 35(5):775–783 (in Chinese). https://doi.org/10.13345/j.cjb.180416
Ge L, Cai Y, Ying F, et al., 2019. miR-181c-5p exacerbates hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting PTPN4. Oxid Med Cell Longev, 2019: 1957920. https://doi.org/10.1155/2019/1957920
Gerken T, Girard CA, Tung YCL, et al., 2007. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318(5855):1469–1472. https://doi.org/10.1126/science.1151710
Gibney ER, Nolan CM, 2010. Epigenetics and gene expression. Heredity (Edinb), 105(1):4–13. https://doi.org/10.1038/hdy.2010.54
Gilbert ER, Liu DM, 2012. Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes. Epigenetics, 7(8):841–852. https://doi.org/10.4161/epi.21238
Grandl G, Wolfrum C, 2018. Hemostasis, endothelial stress, inflammation, and the metabolic syndrome. Semin Immunopathol, 40(2):215–224. https://doi.org/10.1007/s00281-017-0666-5
Guo MJ, Liu XH, Zheng XT, et al., 2017. m6A RNA modification determines cell fate by regulating mRNA degradation. Cell Reprogram, 19(4):225–231. https://doi.org/10.1089/cell.2016.0041
Gustavsson J, Mehlig K, Leander K, et al., 2014. FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women. Circ Cardiovasc Genet, 7(2): 171–177. https://doi.org/10.1161/circgenetics.111.000007
Haupt A, Thamer C, Staiger H, et al., 2009. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes, 117(4):194–197. https://doi.org/10.1055/s-0028-1087176
He C, 2010. Grand challenge commentary: RNA epigenetics? Nat Chem Biol, 6(12):863–865. https://doi.org/10.1038/nchembio.482
He SK, Li XH, Chan N, et al., 2013. Review: epigenetic mechanisms in ocular disease. Mol Vis, 19:665–674.
Henriques JPS, Haasdijk AP, Zijlstra F, et al., 2003. Outcome of primary angioplasty for acute myocardial infarction during routine duty hours versus during off-hours. J Am Coll Cardiol, 41(12):2138–2142. https://doi.org/10.1016/S0735-1097(03)00461-3
Hess ME, Hess S, Meyer KD, et al., 2013. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci, 16(8):1042–1048. https://doi.org/10.1038/nn.3449
Hou N, Wen Y, Yuan X, et al., 2017. Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp Mol Pathol, 103(3):267–275. https://doi.org/10.1016/j.yexmp.2017.11.006
IL6R Genetics Consortium Emerging Risk Factors Collaboration, 2012. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet, 379(9822):1205–1213. https://doi.org/10.1016/s0140-6736(11)61931-4
Iyen B, Qureshi N, Kai J, et al., 2019. Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: a cohort study. Atherosclerosis, 287:8–15. https://doi.org/10.1016/j.atherosclerosis.2019.05.017
James K, Weitzel LRB, Engelman CD, et al., 2003. Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study. BMC Genet, 4:S83. https://doi.org/10.1186/1471-2156-4-s1-s83
Jia GF, Fu Y, Zhao X, et al., 2011. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol, 7(12):885–887. https://doi.org/10.1038/nchembio.687
Jin J, Liu YF, Huang LH, et al., 2019. Advances in epigenetic regulation of vascular aging. Rev Cardiovasc Med, 20(1): 19–25. https://doi.org/10.31083/j.rcm.2019.01.3189
Katada S, Sassone-Corsi P, 2010. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol, 17(12):1414–1421. https://doi.org/10.1038/nsmb.1961
Kennedy EM, Bogerd HP, Kornepati AVR, et al., 2016. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe, 19(5):675–685. https://doi.org/10.1016/j.chom.2016.04.002
Ketelhuth DFJ, Hansson GK, 2016. Adaptive response of T and B cells in atherosclerosis. Circ Res, 118(4):668–678. https://doi.org/10.1161/circresaha.115.306427
Ketelhuth DFJ, Lutgens E, Bäck M, et al., 2019. Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc Res, 115(9): 1385–1392. https://doi.org/10.1093/cvr/cvz166
Khunti K, Davies M, Majeed A, et al., 2015. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care, 38(2):316–322. https://doi.org/10.2337/dc14-0920
Kmietczyk V, Riechert E, Kalinski L, et al., 2019. m6A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Sci Alliance, 2(2):e201800233. https://doi.org/10.26508/lsa.201800233
Koliaki C, Liatis S, Kokkinos A, 2019. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism, 92:98–107. https://doi.org/10.1016/j.metabol.2018.10.011
Kursawe R, Dixit VD, Scherer PE, et al., 2016. A role of the inflammasome in the low storage capacity of the abdominal subcutaneous adipose tissue in obese adolescents. Diabetes, 65(3):610–618. https://doi.org/10.2337/db15-1478
Lee SH, Wolf PL, Escudero R, et al., 2000. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med, 342(9):626–633. https://doi.org/10.1056/nejm200003023420904
Legein B, Janssen EM, Theelen TL, et al., 2015. Ablation of CD8α+ dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice. Sci Rep, 5:15414. https://doi.org/10.1038/srep15414
Li Y, Ma ZQ, Jiang S, et al., 2017. A global perspective on FOXO1 in lipid metabolism and lipid-related diseases. Prog Lipid Res, 66:42–49. https://doi.org/10.1016/j.plipres.2017.04.002
Libby P, Ridker PM, Hansson GK, 2011. Progress and challenges in translating the biology of atherosclerosis. Nature, 473(7347):317–325. https://doi.org/10.1038/nature10146
Libby P, Lichtman AH, Hansson GK, 2013. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity, 38(6):1092–1104. https://doi.org/10.1016/j.immuni.2013.06.009
Lin SB, Choe J, Du P, et al., 2016. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell, 62(3):335–345. https://doi.org/10.1016/j.molcel.2016.03.021
Liu JZ, Yue YN, Han DL, et al., 2014. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol, 10(2):93–95. https://doi.org/10.1038/nchembio.1432
Liu N, Pan T, 2015. RNA epigenetics. Transl Res, 165(1):28–35. https://doi.org/10.1016/j.trsl.2014.04.003
Liu X, Lin L, Li Q, et al., 2019. ERK1/2 communicates GPCR and EGFR signaling pathways to promote CTGF-mediated hypertrophic cardiomyopathy upon Ang-II stimulation. BMC Mol Cell Biol, 20:14. https://doi.org/10.1186/s12860-019-0202-7
Lokody I, 2014. Gene regulation: RNA methylation regulates the circadian clock. Nat Rev Genet, 15(1):3. https://doi.org/10.1038/nrg3638
Lu L, Liu M, Sun RR, et al., 2015. Myocardial infarction: symptoms and treatments. Cell Biochem Biophys, 72(3):865–867. https://doi.org/10.1007/s12013-015-0553-4
Martino T, Arab S, Straume M, et al., 2004. Day/night rhythms in gene expression of the normal murine heart. J Mol Med (Berl), 82(4):256–264. https://doi.org/10.1007/s00109-003-0520-1
Martino TA, Sole MJ, 2009. Molecular time: an often overlooked dimension to cardiovascular disease. Circ Res, 105(11):1047–1061. https://doi.org/10.1161/circresaha.109.206201
Mathiyalagan P, Adamiak M, Mayourian J, et al., 2019. FTO-dependent N6-methyladenosine regulates cardiac function during remodeling and repair. Circulation, 139(4):518–532. https://doi.org/10.1161/circulationaha.118.033794
Mauer J, Luo XB, Blanjoie A, et al., 2017. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature, 541(7637):371–375. https://doi.org/10.1038/nature21022
Mazzio EA, Soliman KFA, 2012. Basic concepts of epigenetics: impact of environmental signals on gene expression. Epigenetics, 7(2):119–130. https://doi.org/10.4161/epi.7.2.18764
McNamara P, Seo SB, Rudic RD, et al., 2001. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell, 105(7):877–889. https://doi.org/10.1016/S0092-8674(01)00401-9
Melkani GC, Panda S, 2017. Time-restricted feeding for prevention and treatment of cardiometabolic disorders. J Physiol, 595(12):3691–3700. https://doi.org/10.1113/jp273094
Meyer KD, Saletore Y, Zumbo P, et al., 2012. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell, 149(7):1635–1646. https://doi.org/10.1016/j.cell.2012.05.003
Meyer KD, Patil DP, Zhou J, et al., 2015. 5′ UTR m6A promotes cap-independent translation. Cell, 163(4):999–1010. https://doi.org/10.1016/j.cell.2015.10.012
Miki T, Xu ZX, Chen-Goodspeed M, et al., 2012. PML regulates PER2 nuclear localization and circadian function. EMBO J, 31(6):1427–1439. https://doi.org/10.1038/emboj.2012.1
Mitrokhin V, Nikitin A, Brovkina O, et al., 2017. Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers. J Inflamm Res, 10:151–160. https://doi.org/10.2147/jir.s141682
Mukamal KJ, Muller JE, Maclure M, et al., 2000. Increased risk of congestive heart failure among infarctions with nighttime onset. Am Heart J, 140(3):438–442. https://doi.org/10.1067/mhj.2000.108830
Nakahata Y, Kaluzova M, Grimaldi B, et al., 2008. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell, 134(2):329–340. https://doi.org/10.1016/j.cell.2008.07.002
Niu YM, Zhao X, Wu YS, et al., 2013. N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genomics Proteomics Bioinformatics, 11(1): 8–17. https://doi.org/10.1016/j.gpb.2012.12.002
Olivieri F, Albertini MC, Orciani M, et al., 2015. DNA damage response (DDR) and senescence: shuttled inflammamiRNAs on the stage of inflammaging. Oncotarget, 6(34): 35509–35521. https://doi.org/10.18632/oncotarget.5899
Ortiz-Barahona A, Villar D, Pescador N, et al., 2010. Genomewide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction. Nucleic Acids Res, 38(7):2332–2345. https://doi.org/10.1093/nar/gkp1205
Panneerdoss S, Eedunuri VK, Yadav P, et al., 2018. Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression. Sci Adv, 4(10):eaar8263. https://doi.org/10.1126/sciadv.aar8263
Parashar NC, Parashar G, Nayyar H, et al., 2018. N6-adenine DNA methylation demystified in eukaryotic genome: from biology to pathology. Biochimie, 144:56–62. https://doi.org/10.1016/j.biochi.2017.10.014
Pastore N, Brady OA, Diab HI, et al., 2016. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy, 12(8):1240–1258. https://doi.org/10.1080/15548627.2016.1179405
Patil DP, Pickering BF, Jaffrey SR, 2018. Reading m6A in the transcriptome: m6A-binding proteins. Trends Cell Biol, 28(2):113–127. https://doi.org/10.1016/j.tcb.2017.10.001
Peña MSB, Rollins A, 2017. Environmental exposures and cardiovascular disease: a challenge for health and development in low-and middle-income countries. Cardiol Clin, 35(1):71–86. https://doi.org/10.1016/j.ccl.2016.09.001
Reese DE, Mikawa T, Bader DM, 2002. Development of the coronary vessel system. Circ Res, 91(9):761–768. https://doi.org/10.1161/01.RES.0000038961.53759.3C
Rodriguez H, Drouin R, Holmquist GP, et al., 1997. A hot spot for hydrogen peroxide-induced damage in the human hypoxia-inducible factor 1 binding site of the PGK 1 gene. Arch Biochem Biophys, 338(2):207–212. https://doi.org/10.1006/abbi.1996.9820
Rodriguez-Rodero S, Fernández-Morera JL, Fernandez AF, et al., 2010. Epigenetic regulation of aging. Discov Med, 10(52):225–233.
Roignant JY, Soller M, 2017. m6A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet, 33(6):380–390. https://doi.org/10.1016/j.tig.2017.04.003
Scuteri A, Sanna S, Chen WM, et al., 2007. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet, 3(7):e115. https://doi.org/10.1371/journal.pgen.0030115
Shen F, Huang W, Huang JT, et al., 2015. Decreased N6-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab, 100(1):E148–E154. https://doi.org/10.1210/jc.2014-1893
Singhal A, Arora G, Sajid A, et al., 2013. Regulation of homocysteine metabolism by Mycobacterium tuberculosis S-adenosylhomocysteine hydrolase. Sci Rep, 3:2264. https://doi.org/10.1038/srep02264
Smart N, Risebro CA, Melville AAD, et al., 2007. Thymosin β-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium. Ann N Y Acad Sci, 1112(1):171–188. https://doi.org/10.1196/annals.1415.000
Smith AJP, Humphries SE, 2009. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev, 20(1):43–59. https://doi.org/10.1016/j.cytogfr.2008.11.006
Smith TG, Robbins PA, Ratcliffe PJ, 2008. The human side of hypoxia-inducible factor. Br J Haematol, 141(3):325–334. https://doi.org/10.1111/j.1365-2141.2008.07029.x
Smith ZD, Chan MM, Mikkelsen TS, et al., 2012. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature, 484(7394):339–344. https://doi.org/10.1038/nature10960
Song HW, Feng X, Zhang H, et al., 2019. METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenationtreated cardiomyocytes. Autophagy, 15(8):1419–1437. https://doi.org/10.1080/15548627.2019.1586246
Souness JE, Stouffer JE, de Sanchez VC, 1982. Effect of N6-methyladenosine on fat-cell glucose metabolism: evidence for two modes of action. Biochem Pharmacol, 31(24): 3961–3971. https://doi.org/10.1016/0006-2952(82)90642-6
Speakman JR, Rance KA, Johnstone AM, 2008. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring), 16(8):1961–1965. https://doi.org/10.1038/oby.2008.318
Tan FL, Moravec CS, Li JB, et al., 2002. The gene expression fingerprint of human heart failure. Proc Natl Acad Sci USA, 99(17):11387–11392. https://doi.org/10.1073/pnas.162370099
Timpson NJ, Emmett PM, Frayling TM, et al., 2008. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr, 88(4):971–978. https://doi.org/10.1093/ajcn/88.4.971
van Wijk B, van den Berg G, Abu-Issa R, et al., 2009. Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein-and fibroblast growth factor-signaling pathways. Circ Res, 105(5):431–441. https://doi.org/10.1161/circresaha.109.203083
Wang CY, Shie SS, Wen MS, et al., 2015. Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism. Sci Signal, 8(407):ra127. https://doi.org/10.1126/scisignal.aab3357
Wang X, He C, 2014. Reading RNA methylation codes through methyl-specific binding proteins. RNA Biol, 11(6):669–672. https://doi.org/10.4161/rna.28829
Wang Y, Li Y, Toth JI, et al., 2014. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol, 16(2):191–198. https://doi.org/10.1038/ncb2902
Weber C, Noels H, 2011. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med, 17(11):1410–1422. https://doi.org/10.1038/nm.2538
Wei CM, Moss B, 1977. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid. Biochemistry, 16(8):1672–1676.
Wei WQ, Ji XY, Guo XQ, et al., 2017. Regulatory role of N6-methyladenosine (m6A) methylation in RNA processing and human diseases. J Cell Biochem, 118(9): 2534–2543. https://doi.org/10.1002/jcb.25967
Wilkins AK, Barton PI, Tidor B, 2007. The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism. PLoS Comput Biol, 3(12):e242. https://doi.org/10.1371/journal.pcbi.0030242
Winter EM, Groot ACGD, 2007. Epicardium-derived cells in cardiogenesis and cardiac regeneration. Cell Mol Life Sci, 64(6):692–703. https://doi.org/10.1007/s00018-007-6522-3
Wong C, Kanetsky P, Raj D, 2008. Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease. Pediatr Nephrol, 23(7):1037–1051. https://doi.org/10.1007/s00467-008-0816-z
Xuan Y, Wang LN, Zhi H, et al., 2016. Association between 3 IL-10 gene polymorphisms and cardiovascular disease risk: systematic review with meta-analysis and trial sequential analysis. Medicine (Baltimore), 95(6):e2846. https://doi.org/10.1097/md.0000000000002846
Yang Y, Shen F, Huang W, et al., 2019. Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. J Clin Endocrinol Metab, 104(3):665–673. https://doi.org/10.1210/jc.2018-00619
Zhong SL, Li HY, Bodi Z, et al., 2008. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell, 20(5):1278–1288. https://doi.org/10.1105/tpc.108.058883
Zhou B, Ma Q, Rajagopal S, et al., 2008. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature, 454(7200):109–113. https://doi.org/10.1038/nature07060
Author information
Authors and Affiliations
Contributions
Kun ZHAO wrote and edited the manuscript. Chuan-xi YANG and Peng LI collated the literature. Wei SUN edited and revised the manuscript. Kun ZHAO and Xiang-qing KONG designed the study. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
Corresponding author
Ethics declarations
Kun ZHAO, Chuan-xi YANG, Peng LI, Wei SUN, and Xiang-qing KONG declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Project supported by the Grants-in-Aid from the Graduate Research and Innovation Projects of Jiangsu Province (No. KYCX181461), China
Rights and permissions
About this article
Cite this article
Zhao, K., Yang, Cx., Li, P. et al. Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system. J. Zhejiang Univ. Sci. B 21, 509–523 (2020). https://doi.org/10.1631/jzus.B1900680
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1631/jzus.B1900680