N6-methyladenine RNA Modification (m6A): An Emerging Regulator of Metabolic Diseases

Author(s): Hui Zhong, Hui-Fang Tang, Yin Kai*

Journal Name: Current Drug Targets

Volume 21 , Issue 11 , 2020

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Graphical Abstract:


N6-methyladenine RNA modification (m6A) is an RNA methylation modification catalyzed by methyltransferase at the 6th position nitrogen atom of adenine (A), which is the most common chemical modification of eukaryotic messenger RNA (mRNA). Recently, m6A has been found to play an important role in the dynamic regulation of RNA, which is crucial for some physiological and pathophysiological processes such as adipogenesis, cell differentiation, and the immune/inflammatory response. Metabolic diseases are a series of chronic inflammatory disorders caused by metabolic dysfunction of proteins, glucose, and lipids. Emerging studies have shown that m6A plays an important role in the process of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) via regulation of glucose/lipid metabolism and the immune/inflammatory response. In this review, we will summarize the role of m6A in metabolic diseases, which may provide new ideas for the prevention and treatment of metabolic diseases.

Keywords: N6-adenine methylation, metabolic diseases, obesity, type 2 diabetes mellitus, cardiovascular diseases.

Roundtree IA, Evans ME, Pan T, He C. Dynamic rna modifications in gene expression regulation. Cell 2017; 169(7): 1187-200.
[http://dx.doi.org/10.1016/j.cell.2017.05.045] [PMID: 28622506]
Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA 1974; 71(10): 3971-5.
[http://dx.doi.org/10.1073/pnas.71.10.3971] [PMID: 4372599]
Visvanathan A, Somasundaram K. mRNA Traffic Control Reviewed: N6-Methyladenosine (m6 A) Takes the Driver’s Seat. BioEssays 2018; 40(1): 40.
[http://dx.doi.org/10.1002/bies.201700093] [PMID: 29205437]
Lu N, Li X, Yu J, et al. Curcumin attenuates lipopolysaccharide-induced hepatic lipid metabolism disorder by modification of m6 a rna methylation in piglets. Lipids 2018; 53(1): 53-63.
[http://dx.doi.org/10.1002/lipd.12023] [PMID: 29488640]
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012; 149(7): 1635-46.
[http://dx.doi.org/10.1016/j.cell.2012.05.003] [PMID: 22608085]
Bokar JA, Rath-Shambaugh ME, Ludwiczak R, Narayan P, Rottman F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J Biol Chem 1994; 269(26): 17697-704.
[PMID: 8021282]
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 2012; 485(7397): 201-6.
[http://dx.doi.org/10.1038/nature11112] [PMID: 22575960]
Batista PJ, Molinie B, Wang J, et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 2014; 15(6): 707-19.
[http://dx.doi.org/10.1016/j.stem.2014.09.019] [PMID: 25456834]
Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol 2014; 16(2): 191-8.
[http://dx.doi.org/10.1038/ncb2902] [PMID: 24394384]
Zhong S, Li H, Bodi Z, et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 2008; 20(5): 1278-88.
[http://dx.doi.org/10.1105/tpc.108.058883] [PMID: 18505803]
Geula S, Moshitch-Moshkovitz S, Dominissini D, et al. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 2015; 347(6225): 1002-6.
[http://dx.doi.org/10.1126/science.1261417] [PMID: 25569111]
Bodi Z, Zhong S, Mehra S, et al. Adenosine Methylation in Arabidopsis mRNA is Associated with the 3′ End and Reduced Levels Cause Developmental Defects. Front Plant Sci 2012; 3: 48.
[http://dx.doi.org/10.3389/fpls.2012.00048] [PMID: 22639649]
Aguilo F, Zhang F, Sancho A, et al. Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. Cell Stem Cell 2015; 17(6): 689-704.
[http://dx.doi.org/10.1016/j.stem.2015.09.005] [PMID: 26526723]
Chen T, Hao YJ, Zhang Y, et al. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015; 16(3): 289-301.
[http://dx.doi.org/10.1016/j.stem.2015.01.016] [PMID: 25683224]
Xu K, Yang Y, Feng GH, et al. Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation. Cell Res 2017; 27(9): 1100-14.
[http://dx.doi.org/10.1038/cr.2017.100] [PMID: 28809392]
Li HB, Tong J, Zhu S, et al. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 2017; 548(7667): 338-42.
[http://dx.doi.org/10.1038/nature23450] [PMID: 28792938]
Lv J, Zhang Y, Gao S, et al. Endothelial-specific m6A modulates mouse hematopoietic stem and progenitor cell development via Notch signaling. Cell Res 2018; 28(2): 249-52.
[http://dx.doi.org/10.1038/cr.2017.143] [PMID: 29148543]
Zhang C, Chen Y, Sun B, et al. m6A modulates haematopoietic stem and progenitor cell specification. Nature 2017; 549(7671): 273-6.
[http://dx.doi.org/10.1038/nature23883] [PMID: 28869969]
Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 2014; 10(2): 93-5.
[http://dx.doi.org/10.1038/nchembio.1432] [PMID: 24316715]
Śledź P, Jinek M. Structural insights into the molecular mechanism of the m(6)A writer complex. eLife 2016; 5: 5.
[http://dx.doi.org/10.7554/eLife.18434] [PMID: 27627798]
Wang P, Doxtader KA, Nam Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol Cell 2016; 63(2): 306-17.
[http://dx.doi.org/10.1016/j.molcel.2016.05.041] [PMID: 27373337]
Wang X, Feng J, Xue Y, et al. Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature 2016; 534(7608): 575-8.
[http://dx.doi.org/10.1038/nature18298] [PMID: 27281194]
Lin Z, Hsu PJ, Xing X, et al. Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. Cell Res 2017; 27(10): 1216-30.
[http://dx.doi.org/10.1038/cr.2017.117] [PMID: 28914256]
Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, et al. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification. Cell Stem cell 2018; 22: 191-205. e199.
Ping XL, Sun BF, Wang L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 2014; 24(2): 177-89.
[http://dx.doi.org/10.1038/cr.2014.3] [PMID: 24407421]
Chen Y, Peng C, Chen J, et al. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer 2019; 18(1): 127.
[http://dx.doi.org/10.1186/s12943-019-1053-8] [PMID: 31438961]
Schwartz S, Mumbach MR, Jovanovic M, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 2014; 8(1): 284-96.
[http://dx.doi.org/10.1016/j.celrep.2014.05.048] [PMID: 24981863]
Patil DP, Chen CK, Pickering BF, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 2016; 537(7620): 369-73.
[http://dx.doi.org/10.1038/nature19342] [PMID: 27602518]
Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. Zc3h13 Regulates Nuclear RNA m(6)A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol Cell 2018; 69(7620): 1028-1038. e1026.
Guo J, Tang HW, Li J, Perrimon N, Yan D. Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex. Proc Natl Acad Sci USA 2018; 115(14): 3674-9.
[http://dx.doi.org/10.1073/pnas.1720945115] [PMID: 29555755]
Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, et al. The U6 snRNA m(6)A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 2017; 169: 824-835. e814.
Mendel M, Chen KM, Homolka D, Gos P, Pandey RR, McCarthy AA. Methylation of Structured RNA by the m(6)A Writer METTL16 Is Essential for Mouse Embryonic Development. Mol Cell 2018; 71: 986-1000. e1011.
Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39(6): 724-6.
[http://dx.doi.org/10.1038/ng2048] [PMID: 17496892]
Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316(5826): 889-94.
[http://dx.doi.org/10.1126/science.1141634] [PMID: 17434869]
Church C, Moir L, McMurray F, et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 2010; 42(12): 1086-92.
[http://dx.doi.org/10.1038/ng.713] [PMID: 21076408]
Zhao X, Yu YT. Detection and quantitation of RNA base modifications. RNA 2004; 10(6): 996-1002.
[http://dx.doi.org/10.1261/rna.7110804] [PMID: 15146083]
Mauer J, Luo X, Blanjoie A, et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 2017; 541(7637): 371-5.
[http://dx.doi.org/10.1038/nature21022] [PMID: 28002401]
Zhao BS, Nachtergaele S, Roundtree IA, He C. Our views of dynamic N6-methyladenosine RNA methylation. RNA 2018; 24(3): 268-72.
[http://dx.doi.org/10.1261/rna.064295.117] [PMID: 29222116]
Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 2011; 7(12): 885-7.
[http://dx.doi.org/10.1038/nchembio.687] [PMID: 22002720]
Tang C, Klukovich R, Peng H, et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells. Proc Natl Acad Sci USA 2018; 115(2): E325-33.
[http://dx.doi.org/10.1073/pnas.1717794115] [PMID: 29279410]
Zheng Q, Hou J, Zhou Y, Li Z, Cao X. The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus. Nat Immunol 2017; 18(10): 1094-103.
[http://dx.doi.org/10.1038/ni.3830] [PMID: 28846086]
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m(6)A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell 2017; 31(10): 591-606.
Zhang C, Zhi WI, Lu H, et al. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget 2016; 7(40): 64527-42.
[http://dx.doi.org/10.18632/oncotarget.11743] [PMID: 27590511]
Xu C, Wang X, Liu K, et al. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat Chem Biol 2014; 10(11): 927-9.
[http://dx.doi.org/10.1038/nchembio.1654] [PMID: 25242552]
Zhang B, zur Hausen A, Orlowska-Volk M, et al. Alternative splicing-related factor YT521: an independent prognostic factor in endometrial cancer. Int J Gynecol Cancer 2010; 20(4): 492-9.
[http://dx.doi.org/10.1111/IGC.0b013e3181d66ffe] [PMID: 20686370]
Hirschfeld M, Zhang B, Jaeger M, et al. Hypoxia-dependent mRNA expression pattern of splicing factor YT521 and its impact on oncological important target gene expression. Mol Carcinog 2014; 53(11): 883-92.
[http://dx.doi.org/10.1002/mc.22045] [PMID: 23765422]
Wang X, Zhao BS, Roundtree IA, et al. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell 2015; 161(6): 1388-99.
[http://dx.doi.org/10.1016/j.cell.2015.05.014] [PMID: 26046440]
Zhao BS, Wang X, Beadell AV, et al. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 2017; 542(7642): 475-8.
[http://dx.doi.org/10.1038/nature21355] [PMID: 28192787]
Ivanova I, Much C, Di Giacomo M, Azzi C, Morgan M, Moreira PN, et al. The RNA m(6)A Reader YTHDF2 Is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell 2017; 67: 1059-1067. e1054
Cai M, Liu Q, Jiang Q, Wu R, Wang X, Wang Y. Loss of m(6) A on FAM134B promotes adipogenesis in porcine adipocytes through m(6) A-YTHDF2-dependent way. IUBMB Life 2018.
Li A, Chen YS, Ping XL, et al. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res 2017; 27(3): 444-7.
[http://dx.doi.org/10.1038/cr.2017.10] [PMID: 28106076]
Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res 2017; 27(3): 315-28.
[http://dx.doi.org/10.1038/cr.2017.15] [PMID: 28106072]
Hsu PJ, Zhu Y, Ma H, et al. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res 2017; 27(9): 1115-27.
[http://dx.doi.org/10.1038/cr.2017.99] [PMID: 28809393]
Tanabe A, Tanikawa K, Tsunetomi M, et al. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett 2016; 376(1): 34-42.
[http://dx.doi.org/10.1016/j.canlet.2016.02.022] [PMID: 26996300]
Abby E, Tourpin S, Ribeiro J, et al. Implementation of meiosis prophase I programme requires a conserved retinoid-independent stabilizer of meiotic transcripts. Nat Commun 2016; 7: 10324.
[http://dx.doi.org/10.1038/ncomms10324] [PMID: 26742488]
Soh YQS, Mikedis MM, Kojima M, Godfrey AK, de Rooij DG, Page DC. Meioc maintains an extended meiotic prophase I in mice. PLoS Genet 2017; 13(4)e1006704
[http://dx.doi.org/10.1371/journal.pgen.1006704] [PMID: 28380054]
Meyer KD, Patil DP, Zhou J, et al. 5′ UTR m(6)A Promotes Cap-Independent Translation. Cell 2015; 163(4): 999-1010.
[http://dx.doi.org/10.1016/j.cell.2015.10.012] [PMID: 26593424]
Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell 2015; 162(6): 1299-308.
[http://dx.doi.org/10.1016/j.cell.2015.08.011] [PMID: 26321680]
Huang H, Weng H, Sun W, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 2018; 20(3): 285-95.
[http://dx.doi.org/10.1038/s41556-018-0045-z] [PMID: 29476152]
Banerji J, Sands J, Strominger JL, Spies T. A gene pair from the human major histocompatibility complex encodes large proline-rich proteins with multiple repeated motifs and a single ubiquitin-like domain. Proc Natl Acad Sci USA 1990; 87(6): 2374-8.
[http://dx.doi.org/10.1073/pnas.87.6.2374] [PMID: 2156268]
Wu R, Li A, Sun B, et al. A novel m6A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res 2019; 29(1): 23-41.
[http://dx.doi.org/10.1038/s41422-018-0113-8] [PMID: 30514900]
Hosono Y, Niknafs YS, Prensner JR, Iyer MK, Dhanasekaran SM, Mehra R, et al. Oncogenic role of thor, a conserved cancer/testis long non-coding RNA. Cell 2017; 171: 1559-1572. e1520
Edupuganti RR, Geiger S, Lindeboom RGH, et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat Struct Mol Biol 2017; 24(10): 870-8.
[http://dx.doi.org/10.1038/nsmb.3462] [PMID: 28869609]
Arguello AE, DeLiberto AN, Kleiner RE. RNA Chemical Proteomics Reveals the N6-Methyladenosine (m6A)-Regulated Protein-RNA Interactome. J Am Chem Soc 2017; 139(48): 17249-52.
[http://dx.doi.org/10.1021/jacs.7b09213] [PMID: 29140688]
Rathmann W, Giani G. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27(10): 2568-9.
[http://dx.doi.org/10.2337/diacare.27.10.2568] [PMID: 15451946]
Wang X, Wu R, Liu Y, Zhao Y, Bi Z, Yao Y, et al. m(6)A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy 2019; 1-15.
Jiang Q, Sun B, Liu Q, et al. MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m6A-YTHDF1-dependent mechanism. FASEB J 2019; 33(2): 2971-81.
[http://dx.doi.org/10.1096/fj.201801393RRR] [PMID: 30339471]
Zhong X, Yu J, Frazier K, Weng X, Li Y, Cham CM, et al. Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m(6)A mRNA Methylation. Cell Rep 2018; 25: 1816-1828. e1814
m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes 2019; 1
Scuteri A, Sanna S, Chen WM, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3(7) e115.
[http://dx.doi.org/10.1371/journal.pgen.0030115] [PMID: 17658951]
Wardle J, Carnell S, Haworth CM, Farooqi IS, O’Rahilly S, Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab 2008; 93(9): 3640-3.
[http://dx.doi.org/10.1210/jc.2008-0472] [PMID: 18583465]
Haupt A, Thamer C, Staiger H, et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes 2009; 117(4): 194-7.
[http://dx.doi.org/10.1055/s-0028-1087176] [PMID: 19053021]
Fischer J, Koch L, Emmerling C, et al. Inactivation of the Fto gene protects from obesity. Nature 2009; 458(7240): 894-8.
[http://dx.doi.org/10.1038/nature07848] [PMID: 19234441]
Merkestein M, Laber S, McMurray F, et al. FTO influences adipogenesis by regulating mitotic clonal expansion. Nat Commun 2015; 6: 6792.
[http://dx.doi.org/10.1038/ncomms7792] [PMID: 25881961]
Zhao X, Yang Y, Sun BF, Zhao YL, Yang YG. FTO and obesity: mechanisms of association. Curr Diab Rep 2014; 14(5): 486.
[http://dx.doi.org/10.1007/s11892-014-0486-0] [PMID: 24627050]
Lappalainen T, Kolehmainen M, Schwab U, et al. Gene expression of FTO in human subcutaneous adipose tissue, peripheral blood mononuclear cells and adipocyte cell line. J Nutrigenet Nutrigenomics 2010; 3(1): 37-45.
[http://dx.doi.org/10.1159/000320732] [PMID: 20948226]
Zhao X, Yang Y, Sun BF, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 2014; 24(12): 1403-19.
[http://dx.doi.org/10.1038/cr.2014.151] [PMID: 25412662]
Ben-Haim MS, Moshitch-Moshkovitz S, Rechavi G. FTO: linking m6A demethylation to adipogenesis. Cell Res 2015; 25(1): 3-4.
[http://dx.doi.org/10.1038/cr.2014.162] [PMID: 25475057]
Zhang M, Zhang Y, Ma J, et al. The Demethylase Activity of FTO (Fat Mass and Obesity Associated Protein) Is Required for Preadipocyte Differentiation. PLoS One 2015; 10(7)e0133788
[http://dx.doi.org/10.1371/journal.pone.0133788] [PMID: 26218273]
Kulyté A, Rydén M, Mejhert N, et al. MTCH2 in human white adipose tissue and obesity. J Clin Endocrinol Metab 2011; 96(10): E1661-5.
[http://dx.doi.org/10.1210/jc.2010-3050] [PMID: 21795451]
Buzaglo-Azriel L, Kuperman Y, Tsoory M, et al. Loss of Muscle MTCH2 Increases Whole-Body Energy Utilization and Protects from Diet-Induced Obesity. Cell Rep 2017; 18(5): 1335-6.
[http://dx.doi.org/10.1016/j.celrep.2017.01.046] [PMID: 28147285]
Yuan Z, Song D, Wang Y. The novel gene pFAM134B positively regulates fat deposition in the subcutaneous fat of Sus scrofa. Biochem Biophys Res Commun 2014; 454(4): 554-9.
[http://dx.doi.org/10.1016/j.bbrc.2014.10.117] [PMID: 25450692]
Tang QQ, Otto TC, Lane MD. Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci USA 2003; 100(1): 44-9.
[http://dx.doi.org/10.1073/pnas.0137044100] [PMID: 12502791]
Kobayashi M, Ohsugi M, Sasako T, et al. The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis. Mol Cell Biol 2018; 38(16): 38.
[http://dx.doi.org/10.1128/MCB.00116-18] [PMID: 29866655]
Liu Q, Zhao Y, Wu R, et al. ZFP217 regulates adipogenesis by controlling mitotic clonal expansion in a METTL3-m6A dependent manner. RNA Biol 2019; 16(12): 1785-93.
[http://dx.doi.org/10.1080/15476286.2019.1658508] [PMID: 31434544]
Yao Y, Bi Z, Wu R, et al. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m6A-YTHDF2-dependent manner. FASEB J 2019; 33(6): 7529-44.
[http://dx.doi.org/10.1096/fj.201802644R] [PMID: 30865855]
Abd El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: The diagnosis and management. World J Hepatol 2015; 7(6): 846-58.
[http://dx.doi.org/10.4254/wjh.v7.i6.846] [PMID: 25937862]
Asgharpour A, Cazanave SC, Pacana T, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol 2016; 65(3): 579-88.
[http://dx.doi.org/10.1016/j.jhep.2016.05.005] [PMID: 27261415]
Luo Z, Zhang Z, Tai L, Zhang L, Sun Z, Zhou L. Comprehensive analysis of differences of N6-methyladenosine RNA methylomes between high-fat-fed and normal mouse livers. Epigenomics 2019; 11(11): 1267-82.
[http://dx.doi.org/10.2217/epi-2019-0009] [PMID: 31290331]
Lim U, Ernst T, Wilkens LR, et al. Susceptibility variants for waist size in relation to abdominal, visceral, and hepatic adiposity in postmenopausal women. J Acad Nutr Diet 2012; 112(7): 1048-55.
[http://dx.doi.org/10.1016/j.jand.2012.03.034] [PMID: 22889634]
Guo J, Ren W, Li A, et al. Fat mass and obesity-associated gene enhances oxidative stress and lipogenesis in nonalcoholic fatty liver disease. Dig Dis Sci 2013; 58(4): 1004-9.
[http://dx.doi.org/10.1007/s10620-012-2516-6] [PMID: 23329013]
Khovidhunkit W, Kim MS, Memon RA, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004; 45(7): 1169-96.
[http://dx.doi.org/10.1194/jlr.R300019-JLR200] [PMID: 15102878]
Asher G, Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 2015; 161(1): 84-92.
[http://dx.doi.org/10.1016/j.cell.2015.03.015] [PMID: 25815987]
Fustin JM, Kojima R, Itoh K, et al. Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock. Proc Natl Acad Sci USA 2018; 115(23): 5980-5.
[http://dx.doi.org/10.1073/pnas.1721371115] [PMID: 29784786]
Wang X, Zhu L, Chen J, Wang Y. mRNA m6A methylation downregulates adipogenesis in porcine adipocytes. Biochem Biophys Res Commun 2015; 459(2): 201-7.
[http://dx.doi.org/10.1016/j.bbrc.2015.02.048] [PMID: 25725156]
Yadav PK, Rajasekharan R. The m6A methyltransferase Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology in haploid yeast cells. J Biol Chem 2017; 292(33): 13727-44.
[http://dx.doi.org/10.1074/jbc.M117.783761] [PMID: 28655762]
Yadav PK, Rajvanshi PK, Rajasekharan R. The role of yeast m6A methyltransferase in peroxisomal fatty acid oxidation. Curr Genet 2018; 64(2): 417-22.
[http://dx.doi.org/10.1007/s00294-017-0769-5] [PMID: 29043484]
Mo X, Lei S, Zhang Y, Zhang H. Genome-wide enrichment of m(6)A-associated single-nucleotide polymorphisms in the lipid loci. Pharmacogenomics J 2018.
[PMID: 30262821]
Souness JE, Stouffer JE, Chagoya de Sanchez V. Effect of N6-methyladenosine on fat-cell glucose metabolism. Evidence for two modes of action. Biochem Pharmacol 1982; 31(24): 3961-71.
[http://dx.doi.org/10.1016/0006-2952(82)90642-6] [PMID: 6297505]
Shen F, Huang W, Huang JT, et al. Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab 2015; 100(1): E148-54.
[http://dx.doi.org/10.1210/jc.2014-1893] [PMID: 25303482]
Yang Y, Shen F, Huang W, et al. Glucose Is Involved in the Dynamic Regulation of m6A in Patients with Type 2 Diabetes. J Clin Endocrinol Metab 2019; 104(3): 665-73.
[http://dx.doi.org/10.1210/jc.2018-00619] [PMID: 30137347]
Li Y, Ma Z, Jiang S, et al. A global perspective on FOXO1 in lipid metabolism and lipid-related diseases. Prog Lipid Res 2017; 66: 42-9.
[http://dx.doi.org/10.1016/j.plipres.2017.04.002] [PMID: 28392404]
Kursawe R, Dixit VD, Scherer PE, et al. A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 2016; 65(3): 610-8.
[http://dx.doi.org/10.2337/db15-1478] [PMID: 26718495]
Farah BL, Landau DJ, Sinha RA, et al. Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. J Hepatol 2016; 64(2): 370-9.
[http://dx.doi.org/10.1016/j.jhep.2015.10.008] [PMID: 26462884]
Jornayvaz FR, Birkenfeld AL, Jurczak MJ, et al. Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc Natl Acad Sci USA 2011; 108(14): 5748-52.
[http://dx.doi.org/10.1073/pnas.1103451108] [PMID: 21436037]
Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem 2009; 55(3): 425-38.
[http://dx.doi.org/10.1373/clinchem.2008.115352] [PMID: 19181734]
Xie W, Ma LL, Xu YQ, Wang BH, Li SM. METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism. Biochem Biophys Res Commun 2019; 518(1): 120-6.
[http://dx.doi.org/10.1016/j.bbrc.2019.08.018] [PMID: 31405565]
Chen XY, Zhang J, Zhu JS. The role of m6A RNA methylation in human cancer. Mol Cancer 2019; 18(1): 103.
[http://dx.doi.org/10.1186/s12943-019-1033-z] [PMID: 31142332]
Gokhale NS, McIntyre ABR, McFadden MJ, et al. N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. Cell Host Microbe 2016; 20(5): 654-65.
[http://dx.doi.org/10.1016/j.chom.2016.09.015] [PMID: 27773535]
Zhao X, Chen Y, Mao Q, et al. Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Biomark 2018; 21(4): 859-68.
[http://dx.doi.org/10.3233/CBM-170791] [PMID: 29439311]
Benitez CM, Qu K, Sugiyama T, et al. An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development. PLoS Genet 2014; 10(10) e1004645.
[http://dx.doi.org/10.1371/journal.pgen.1004645] [PMID: 25330008]
Song W, Li Q, Wang L, Wang L. Modulation of FoxO1 expression by miR-21 to promote growth of pancreatic ductal adenocarcinoma. Cell Physiol Biochem 2015; 35(1): 184-90.
[http://dx.doi.org/10.1159/000369686] [PMID: 25591761]
Boissel S, Reish O, Proulx K, et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 2009; 85(1): 106-11.
[http://dx.doi.org/10.1016/j.ajhg.2009.06.002] [PMID: 19559399]
Gustavsson J, Mehlig K, Leander K, et al. FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women. Circ Cardiovasc Genet 2014; 7(2): 171-7.
[http://dx.doi.org/10.1161/CIRCGENETICS.111.000007] [PMID: 24622111]
Äijälä M, Ronkainen J, Huusko T, et al. The fat mass and obesity-associated (FTO) gene variant rs9939609 predicts long-term incidence of cardiovascular disease and related death independent of the traditional risk factors. Ann Med 2015; 47(8): 655-63.
[http://dx.doi.org/10.3109/07853890.2015.1091088] [PMID: 26555680]
Mo XB, Lei SF, Zhang YH, Zhang H. Detection of m6A-associated SNPs as potential functional variants for coronary artery disease. Epigenomics 2018; 10(10): 1279-87.
[http://dx.doi.org/10.2217/epi-2018-0007] [PMID: 30221544]
Zhang Y, Guo F, Zhao R. Hepatic expression of FTO and fatty acid metabolic genes changes in response to lipopolysaccharide with alterations in m6A modification of relevant mRNAs in the chicken. Br Poult Sci 2016; 57(5): 628-35.
[http://dx.doi.org/10.1080/00071668.2016.1201199] [PMID: 27398647]
Carnevali L, Graiani G, Rossi S, et al. Signs of cardiac autonomic imbalance and proarrhythmic remodeling in FTO deficient mice. PLoS One 2014; 9(4) e95499.
[http://dx.doi.org/10.1371/journal.pone.0095499] [PMID: 24743632]
Mathiyalagan P, Adamiak M, Mayourian J, et al. FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation 2019; 139(4): 518-32.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033794] [PMID: 29997116]
Hess ME, Hess S, Meyer KD, et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 2013; 16(8): 1042-8.
[http://dx.doi.org/10.1038/nn.3449] [PMID: 23817550]
Wang X, Huang N, Yang M, et al. FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis. Cell Death Dis 2017; 8(3)e2702
[http://dx.doi.org/10.1038/cddis.2017.122] [PMID: 28333151]
Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling. Cell 2018; 172: 90-105.e123
Dorn LE, Lasman L, Chen J, et al. The N6-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy. Circulation 2019; 139(4): 533-45.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036146] [PMID: 30586742]
Kmietczyk V, Riechert E, Kalinski L, Boileau E, Malovrh E, Malone B. m(6)A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Sci Alliance 2019; 2: e201800233.

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Year: 2020
Published on: 18 September, 2020
Page: [1056 - 1067]
Pages: 12
DOI: 10.2174/1389450121666200210125247
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