Research Progress on Biological Function Growth and Development Related to N6-methyladenosine in Mammals

doi:10.13560/j.cnki.biotech.bull.1985.2020-1358

Abstract

Abstract:

Epigenetic modification of RNA N6-methyladenine（m⁶A）is the most extensive intermediate chemical modification in RNA,which exists commonly in living organisms,especially in mammals. The discovery of m⁶A modifying enzymes and binding proteins confirmed that RNA methylation modification is a dynamic reversible process,and the common m⁶A modifying enzymes mainly include methyltransferase and demethylase. Recent studies have successively found that m⁶A modification level and m⁶A distribution on RNA affect the processes of mRNA splicing,translation,stability,and exporting. RNA methylation-mediated epitranscriptomics is involved in many biological processes. This review summarizes the major m⁶A methylation modification of enzyme,the detection method and m⁶A biological functions in embryonic development,muscle development,as well as lipogenesis based on the latest m⁶A research,aiming to find new directions for exploring the functions and regulatory mechanisms of m⁶A methylation modification in important biological processes in animals.

Key words: N6-methyladenosine, epigenetic, regulation, biological function

XUE Xiang-lan, DING Yang-yang, LIU Yue, LI Xiao-bo, JIANG Lin, HE Xiao-hong, MA Yue-hui, ZHAO Qian-jun. Research Progress on Biological Function Growth and Development Related to N6-methyladenosine in Mammals[J]. Biotechnology Bulletin, 2021, 37(4): 251-259.

Figures/Tables 3

References 67

[1]	Yoon KJ, Ringeling FR, Vissers C, et al. Temporal control of mammalian cortical neurogenesis by m⁶A methylation[J]. Cell, 2017, 171(4):877-889.e17. doi: 10.1016/j.cell.2017.09.003 URL
[2]	Shi H, Zhang X, Weng YL, et al. m⁶A facilitates hippocampus-dependent learning and memory through YTHDF1[J]. Nature, 2018,563(7730):249-253. doi: 10.1038/s41586-018-0666-1 URL
[3]	Zhu B, Gong Y, Shen L, et al. Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m⁶A modulation[J]. Biomed Pharmacother, 2020,124:109935. doi: 10.1016/j.biopha.2020.109935 URL
[4]	Tanaka T, Weisblum B. Systematic difference in the methylation of ribosomal ribonucleic acid from gram-positive and gram-negative bacteria[J]. J Bacteriol, 1975,123(2):771-774. pmid: 807565
[5]	Munns TW, Sims HF, Liszewski MK. Immunospecific retention of oligonucleotides possessing N6-methyladenosine and 7-methylguanosine[J]. J Biol Chem, 1977,252(9):3102-3104. pmid: 323262
[6]	Epstein P, Reddy R, Henning D, et al. The nucleotide sequence of nuclear U6(4. 7 S)RNA[J]. J Biol Chem, 1980,255(18):8901-8906. pmid: 6773955
[7]	Donald TD, Robert HT. The methylation state of poly A-containing- messenger RNA from cultured hamster cells[J]. Nucleic Acids Research, 1975,2(10):1653-1668. doi: 10.1093/nar/2.10.1653 URL
[8]	Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al. Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq[J]. Nature, 2012,485(7397):201-206. doi: 10.1038/nature11112 pmid: 22575960
[9]	Meyer KD, Saletore Y, Zumbo P, et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons[J]. Cell, 2012,149(7):1635-1646. doi: 10.1016/j.cell.2012.05.003 pmid: 22608085
[10]	Jia G, Fu Y, He C. Reversible RNA adenosine methylation in biological regulation[J]. Trends in Genetics, 2013,29(2):108-115. doi: 10.1016/j.tig.2012.11.003 URL
[11]	Alarcón C R, Goodarzi H, Lee H, et al. HNRNPA2B1 is a mediator of m⁶A-dependent nuclear RNA processing events[J]. Cell, 2015,162(6):1299-1308. doi: 10.1016/j.cell.2015.08.011 URL
[12]	Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J]. Nature Chemical Biology, 2014,10(2):93-95. doi: 10.1038/nchembio.1432 URL
[13]	Dai D, Wang H, Zhu L, et al. N⁶-methyladenosine links RNA metabolism to cancer progression[J]. Cell Death & Disease, 2018,9(2):124.
[14]	Bokar JA, Shambaugh ME, Polayes D, et al. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA(N6-adenosine)-methyltransferase[J]. RNA, 1997,3(11):1233-1247. pmid: 9409616
[15]	Zhang C, Chen Y, Sun B, et al. m⁶A modulates haematopoietic stem and progenitor cell specification[J]. Nature, 2017,549(7671):273-276. doi: 10.1038/nature23883 URL
[16]	Wang Y, Li Y, Toth JI, et al. N⁶-methyladenosine modification destabilizes developmental regulators in embryonic stem cells[J]. Nature Cell Biology, 2014,16(2):191-198. doi: 10.1038/ncb2902 URL
[17]	Ping XL, Sun BF, Wang L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Research, 2014,24(2):177-189. doi: 10.1038/cr.2014.3 URL
[18]	Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases[J]. Mol Cell, 2016,63(2):306-317. doi: 10.1016/j.molcel.2016.05.041 URL
[19]	Schwartz S, Mumbach M, Jovanovic M, et al. Perturbation of m⁶A writers reveals two distinct classes of mRNA methylation at internal and 5' sites[J]. Cell Reports, 2014,8(1):284-296. doi: 10.1016/j.celrep.2014.05.048 pmid: 24981863
[20]	Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m⁶A over ALKBH5[J]. Nucleic Acids Res, 2015,43(1):373-384. doi: 10.1093/nar/gku1276 URL
[21]	Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to childhood obesity and severe adult obesity[J]. Nat Genet, 2007,39(6):724-726. doi: 10.1038/ng2048 URL
[22]	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[J]. Science, 2007,316(5826):889-894. doi: 10.1126/science.1141634 URL
[23]	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[J]. PLoS Genet, 2007,3(7):e115. doi: 10.1371/journal.pgen.0030115 URL
[24]	Jia GF, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J]. Nature Chemical Biology, 2011,7(12):885-887. doi: 10.1038/nchembio.687 URL
[25]	Alarcón CR, Hyeseung L, Hani G, et al. N⁶-methyladenosine marks primary microRNAs for processing[J]. Nature, 2015,519(7544):482-485. doi: 10.1038/nature14281 URL
[26]	Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014,505(7481):117-120. doi: 10.1038/nature12730 URL
[27]	Liu S, Li G, Li Q, et al. The roles and mechanisms of YTH domain-containing proteins in cancer development and progression[J]. American Journal of Cancer Research, 2020,10(4):1068-1084.
[28]	Liu N, Dai Q, Zheng GQ, et al. N⁶-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature, 2015,518(7540):560-564. doi: 10.1038/nature14234 URL
[29]	Meyer KD, Patil DP, Zhou J, et al. 5' UTR m⁶A promotes Cap-independent translation[J]. Cell, 2015,163(4):999-1010. doi: 10.1016/j.cell.2015.10.012 pmid: 26593424
[30]	Li A, Chen YS, Ping XL, et al. Cytoplasmic m⁶A reader YTHDF3 promotes mRNA translation[J]. Cell Res, 2017,27(3):444-447. doi: 10.1038/cr.2017.10 URL
[31]	Kasowitz SD, Ma J, Anderson SJ, et al. Nuclear m⁶A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development[J]. PLoS Genetics, 2018,14(5):e1007412. doi: 10.1371/journal.pgen.1007412 URL
[32]	Lee M, Kim B, Kim VN. Emerging roles of RNA modification:m⁶A and U-tail[J]. Cell, 2014,158(5):980-987. doi: 10.1016/j.cell.2014.08.005 URL
[33]	Wang Y, Li Y, Yue M, et al. N⁶-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications[J]. Nature Neuroscience, 2018,21(2):195-206. doi: 10.1038/s41593-017-0057-1 URL
[34]	Fu Y, Dominissini D, Rechavi G, et al. Gene expression regulation mediated through reversible m⁶A RNA methylation[J]. Nature Reviews Genetics, 2014,15(5):293-306. doi: 10.1038/nrg3724 URL
[35]	da Silva DVT, Baião DDS, de Oliveira Silva F, et al. Betanin, a natural food additive:stability, bioavailability, antioxidant and preservative ability assessments[J]. Molecules, 2019,24(3):458. doi: 10.3390/molecules24030458 URL
[36]	Arivazhagan A, Arora A, Hegde AS, et al. Essential role of METTL3-mediated m⁶A modification in glioma stem-like cells maintenance and radioresistance[J]. Oncogene, 2018,37(4):522-533. doi: 10.1038/onc.2017.351 URL
[37]	Wei CM, Moss B. Methylation of newly synthesized viral messenger RNA by an enzyme in vaccinia virus[J]. National Academy of Sciences, 1974,71(8):3014-3018. doi: 10.1073/pnas.71.8.3014 URL
[38]	Rottman FM, Desrosiers RC, Friderici K. Nucleotide methylation patterns in eukaryotic mRNA[J]. Chinese Bulletin of Life Sciences, 1976,19:539-550.
[39]	Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from novikoff hepatoma cells[J]. National Academy of Sciences, 1974,71(10):3971-3975. doi: 10.1073/pnas.71.10.3971 URL
[40]	Salditt-Georgieff M, Jelinek W, Darnell JE, et al. Methyl labeling of HeLa cell hnRNA:a comparison with mRNA[J]. Cell, 1976,7(2):227-237. pmid: 954080
[41]	Feng Z, Li Q, Meng R, et al. METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide-induced inflammatory response in human dental pulp cells[J]. Journal of Cellular and Molecular Medicine, 2018,22(54):2558-2568. doi: 10.1111/jcmm.2018.22.issue-5 URL
[42]	Fleith RC, Mears HV, Leong XY, et al. IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA[J]. Nucleic Acids Research, 2018,46(10):5269-5285. doi: 10.1093/nar/gky191 URL
[43]	Huang H, Weng H, Sun W, et al. Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation[J]. Nature Cell Biology, 2018,20(3):285-295. doi: 10.1038/s41556-018-0045-z URL
[44]	Zhang Z, Chen LQ, Zhao YL, et al. Single-base mapping of m⁶A by an antibody-independent method[J]. Science Advances, 2019, 5(7):eaax0250. doi: 10.1126/sciadv.aax0250 URL
[45]	Garcia-Campos MA, Edelheit S, Toth U, et al. Deciphering the “m⁶A Code” via antibody-independent quantitative profiling[J]. Cell, 2019, 178(3):731-747. e16. doi: S0092-8674(19)30676-2 pmid: 31257032
[46]	Ortega A, Niksic M, Bachi A, et al. Biochemical function of female-lethal(2)D/wilms’ tumor suppressor-1-associated proteins in alternative pre-mRNA splicing[J]. Journal of Biological Chemistry, 2003,278(5):3040-3047. doi: 10.1074/jbc.M210737200 URL
[47]	Batista PJ, Molinie B, Wang J, et al. m⁶A RNA modification controls cell fate transition in mammalian embryonic stem cells[J]. Cell Stem Cell, 2014,15(6):707-719. doi: 10.1016/j.stem.2014.09.019 pmid: 25456834
[48]	Xiao S, Cao S, Huang Q, et al. The RNA N⁶-methyladenosine modification landscape of human fetal tissues[J]. Nature Cell Biology, 2019,21(5):651-661. doi: 10.1038/s41556-019-0315-4 URL
[49]	Batista PJ, Ruby JG, Claycomb JM, et al. PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans[J]. Molecular Cell, 2008,31(1):67-78. doi: 10.1016/j.molcel.2008.06.002 pmid: 18571452
[50]	Geula S, Moshitch-Moshkovitz S, Dominissini D, et al. m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation[J]. Science, 2015,347(6225):1002-1006. doi: 10.1126/science.1261417 URL
[51]	Deangelis AM, Martini AE, Owen CM. Assisted reproductive tech-nology and epigenetics[J]. Semin Reprod Med, 2018,36(3/4):221-232. doi: 10.1055/s-0038-1675780 URL
[52]	Lin Z, Hsu PJ, Xing X, et al. Mettl3-/Mettl14-mediated mRNA N⁶-methyladenosine modulates murine spermatogenesis[J]. Cell Research, 2017,27(10):1216-1230. doi: 10.1038/cr.2017.117 URL
[53]	Xu K, Yang Y, Feng GH, et al. Mettl3-mediated m⁶A regulates spermatogonial differentiation and meiosis initiation[J]. Cell Research, 2017,27(9):1100-1114. doi: 10.1038/cr.2017.100 URL
[54]	Luo Z, Zhang Z, Tai L, et al. Comprehensive analysis of differences of N⁶-methyladenosine RNA methylomes between high-fat-fed and normal mouse livers[J]. Epigenomics, 2019,11:1267-1282. doi: 10.2217/epi-2019-0009 URL
[55]	Zhao YL, Liu YH, Wu RF, et al. Understanding m⁶A function through uncovering the diversity roles of YTH domain-containing proteins[J]. Molecular Biotechnology, 2019,61(5):355-364. doi: 10.1007/s12033-018-00149-z pmid: 30637606
[56]	Wang X, Sun B, Jiang Q, et al. mRNA m⁶A plays opposite role in regulating UCP2 and PNPLA2 protein expression in adipocytes[J]. Int J Obes(Lond), 2018,42(11):1912-1924. doi: 10.1038/s41366-018-0027-z URL
[57]	Wang X, Wu R, Liu Y, et al. m⁶A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7[J]. Autophagy, 2019: 1-15.
[58]	Wu Y, Xie L, Wang M, et al. Mettl3-mediated m⁶A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis[J]. Nat Commun, 2018,9(1):4772. doi: 10.1038/s41467-018-06898-4 URL
[59]	Li X, Yang J, Zhu Y, et al. Mouse maternal high-fat intake dynamically programmed mRNA m⁶A modifications in adipose and skeletal muscle tissues in offspring[J]. Int J Mol Sci, 2016,17(8).
[60]	Liu J, Luo G, Sun J, et al. METTL14 is essential for β-cell survival and insulin secretion[J]. Biochim Biophys Acta Mol Basis Dis, 2019,1865(9):2138-2148. doi: 10.1016/j.bbadis.2019.04.011 URL
[61]	Kudou K, Komatsu T, Nogami J, et al. The requirement of Mettl3-promoted MyoD mRNA maintenance in proliferative myoblasts for skeletal muscle differentiation[J]. Open Biology, 7(9):170119.
[62]	Chen JN, Chen Y, Wei YY, et al. Regulation of m⁶A RNA methylation and its effect on myogenic differentiation in murine myoblasts[J]. Mol Biol(Mosk), 2019,53(3):436-445.
[63]	Wang X, Huang N, Yang M, et al. FTO is required for myogenesis by positively regulating mTOR-PGC-1alpha pathway-mediated mitochondria biogenesis[J]. Cell Death Dis, 2017,8(3):e2702. doi: 10.1038/cddis.2017.122 URL
[64]	Mathiyalagan P, Adamiak M, Mayourian J, et al. FTO-dependent N⁶-methyladenosine regulates cardiac function during remodeling and repair[J]. Circulation, 2019,139(4):518-532. doi: 10.1161/CIRCULATIONAHA.118.033794 pmid: 29997116
[65]	Dorn LE, Lasman L, Chen J, et al. The N⁶-Methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy[J]. Circulation, 2019,139(4):533-545. doi: 10.1161/CIRCULATIONAHA.118.036146 URL
[66]	Kmietczyk V, Riechert E, Kalinski L, et al. m⁶A-mRNA methylation regulates cardiac gene expression and cellular growth[J]. Life Science Alliance, 2019,2(2):e201800233. doi: 10.26508/lsa.201800233 URL
[67]	Lin J, Zhu Q, Huang J, et al. Hypoxia promotes vascular smooth muscle cell(VSMC)differentiation of adipose-derived stem cell(ADSC)by regulating mettl3 and paracrine factors[J]. Stem Cells International, 2020,2020:2830565.

检测方法 Detection method	优点 Advantage	缺点 Defect	参考文献 Reference
比色法 Colorimetry	RNA整体水平检测、成本低、操作简单	不具备特异性、低通量	[32]
MeRIP-Seq	高通量、单碱基、高灵敏度、量化转录片段	依赖抗体、无法定量、无法在全转录组水平精确定位	[33-34]
HPLC-LC/MS/MS	快速、灵敏、分辨率高、可准确定量定性分析	定性能力较弱、检测灵敏度一般	[35]
m⁶A-miCLIP	高通量、单碱基、UV诱导抗体-RNA交联	依赖于抗体	[36]
PA-m⁶A-Seq	高通量、单碱基、细胞水平定位	依赖于抗体	[46]
m⁶A-LAIC-Seq	高通量、精确定量	依赖于抗体	[36]
m⁶A-REF-Seq/ MAZTER-Seq	不依赖于抗体、特异性区分m⁶A修饰的内切核酸酶、高通量	不能覆盖所有m⁶A位点	[44-45]

检测方法 Detection method	优点 Advantage	缺点 Defect	参考文献 Reference
比色法 Colorimetry	RNA整体水平检测、成本低、操作简单	不具备特异性、低通量	[32]
MeRIP-Seq	高通量、单碱基、高灵敏度、量化转录片段	依赖抗体、无法定量、无法在全转录组水平精确定位	[33-34]
HPLC-LC/MS/MS	快速、灵敏、分辨率高、可准确定量定性分析	定性能力较弱、检测灵敏度一般	[35]
m⁶A-miCLIP	高通量、单碱基、UV诱导抗体-RNA交联	依赖于抗体	[36]
PA-m⁶A-Seq	高通量、单碱基、细胞水平定位	依赖于抗体	[46]
m⁶A-LAIC-Seq	高通量、精确定量	依赖于抗体	[36]
m⁶A-REF-Seq/ MAZTER-Seq	不依赖于抗体、特异性区分m⁶A修饰的内切核酸酶、高通量	不能覆盖所有m⁶A位点	[44-45]