N6-甲基腺苷修饰对女性生殖系统功能的影响

doi:10.16288/j.yczz.23-071

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Hereditas(Beijing) ›› 2023, Vol. 45 ›› Issue (6): 472-487.doi: 10.16288/j.yczz.23-071

• Review • Previous Articles Next Articles

Effects of N⁶-methyladenosine modification on the function of the female reproductive system

Shan He(), Jian Zhao(), Xiaofeng Song()

College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China

Received:2023-03-23 Revised:2023-05-12 Online:2023-06-20 Published:2023-05-17
Contact: Zhao Jian,Song Xiaofeng E-mail:heshan@nuaa.edu.cn;xfsong@nuaa.edu.cn;zhaojian@nuaa.edu.cn
Supported by:
Key R&D Plan Projects in Jiangsu Province(BE2022843);National Natural Science Foundation of China(62273175);National Natural Science Foundation of China(62003165);National Natural Science Foundation of China(61973155)

Abstract

Abstract:

In recent years, the rate of female infertility in China has been increasing, posing an urgent challenge to improve fertility. A healthy reproductive system is essential for successful reproduction, and N⁶-methyladenosine (m⁶A) is the most abundant chemical modification in eukaryotes and plays a critical role in cellular processes. Recent studies have shown that m⁶A modifications also have a keying effect in various physiological and pathological processes in the female reproductive system, although their regulatory mechanisms and biological functions remain unclear. In this review, we first introduce the reversible regulatory mechanisms of m⁶A and its functions, discuss the role of m⁶A in female reproductive function and disorders of the reproductive system, and present recent advances in m⁶A detection technologies and methods. Our review provides new insights into the biological role of m⁶A and its potential application in the treatment of female reproductive disorders.

Key words: m⁶A, methylation modification, female reproductive system, development and aging, diseases

Shan He, Jian Zhao, Xiaofeng Song. Effects of N⁶-methyladenosine modification on the function of the female reproductive system[J]. Hereditas(Beijing), 2023, 45(6): 472-487.

Figures/Tables 6

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References 96

[1]	Tatone C, Amicarelli F. The aging ovary—the poor granulosa cells. Fertil Steril. 2013, 99(1): 12-17. doi: S0015-0282(12)02441-7 pmid: 23273984
[2]	He MN, Zhang T, Yang Y, Wang C. Mechanisms of oocyte maturation and related epigenetic regulation. Front Cell Dev Biol, 2021, 9: 654028. doi: 10.3389/fcell.2021.654028
[3]	An SQ, Huang WX, Huang X, Cun YX, Cheng WS, Sun X, Ren ZJ, Chen YX, Chen WF, Wang JK. Integrative network analysis identifies cell-specific trans regulators of m⁶A. Nucleic Acids Res, 2020, 48(4): 1715-1729. doi: 10.1093/nar/gkz1206 pmid: 31912146
[4]	Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m⁶A RNA methylation. Nat Rev Genet, 2014, 15(5): 293-306. doi: 10.1038/nrg3724
[5]	Zhang X, Jia GF. RNA epigenetic modification: N⁶-methyladenosine. Hereditas (Beijing), 2016, 38(4): 275-288.
	张笑, 贾桂芳. RNA表观遗传修饰:N⁶-甲基腺嘌呤. 遗传, 2016, 38(4): 275-288.
[6]	Zeng CW, Huang WX, Li YQ, Weng HY. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol, 2020, 13(1): 117. doi: 10.1186/s13045-020-00951-w
[7]	Wang X, Feng J, Xue Y, Guan YZ, Zhang DL, Liu Z, Gong Z, Wang Q, Huang JB, Tang C, Zou TT, Yin P. Structural basis of N⁶-adenosine methylation by the METTL3-METTL14 complex. Nature, 2016, 534(7608): 575-578. doi: 10.1038/nature18298
[8]	Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol, 2017, 18(1): 31-42.
[9]	Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N⁶-methyladenosine methyltransferase. Cell Res, 2014, 24(2): 177-189. doi: 10.1038/cr.2014.3 pmid: 24407421
[10]	Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, Sanjana NE, Freinkman E, Pacold ME, Satija R, Mikkelsen TS, Hacohen N, Zhang F, Carr SA, Lander ES, Regev A. Perturbation of m⁶A writers reveals two distinct classes of mRNA methylation at internal and 5' sites. Cell Rep, 2014, 8(1): 284-296. doi: 10.1016/j.celrep.2014.05.048 pmid: 24981863
[11]	Wen J, Lv RT, Ma HH, Shen HJ, He CX, Wang JH, Jiao FF, Liu H, Yang PY, Tan L, Lan F, Shi YG, He C, Shi Y, Diao JB. Zc3h13 regulates nuclear RNA m⁶A methylation and mouse embryonic stem cell self-renewal. Mol Cell, 2018, 69(6): 1028-1038.e6. doi: 10.1016/j.molcel.2018.02.015
[12]	Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR. m⁶A RNA methylation promotes XIST-mediated transcriptional repression. Nature, 2016, 537(7620): 369-373. doi: 10.1038/nature19342
[13]	Jia GF, Fu Y, Zhao X, Dai Q, Zheng GQ, Yang Y, Yi CQ, Lindahl T, Pan T, Yang YG, He C. N⁶-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol, 2011, 7(12): 885-887. doi: 10.1038/nchembio.687 pmid: 22002720
[14]	Zheng GQ, Dahl JA, Niu YM, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu ZK, Bosmans RPG, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia GF, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell, 2013, 49(1): 18-29. doi: 10.1016/j.molcel.2012.10.015 pmid: 23177736
[15]	Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li YJ, Lu ZK, He C, Min JR. Structural basis for selective binding of m⁶A RNA by the YTHDC1 YTH domain. Nat Chem Biol, 2014, 10(11): 927-929. doi: 10.1038/nchembio.1654 pmid: 25242552
[16]	Mao YH, Dong LM, Liu XM, Guo JY, Ma HH, Shen B, Qian SB.m⁶A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2. Nat Commun, 2019, 10(1): 5332. doi: 10.1038/s41467-019-13317-9
[17]	Liu T, Wei QL, Jin J, Luo QY, Liu Y, Yang Y, Cheng CM, Li LF, Pi JN, Si YM, Xiao HL, Li L, Rao S, Wang F, Yu JH, Yu J, Zou DL, Yi P. The m⁶A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res, 2020, 48(7): 3816-3831. doi: 10.1093/nar/gkaa048 pmid: 31996915
[18]	Wang X, Zhao BS, Roundtree IA, Lu ZK, Han DL, Ma HH, Weng XC, Chen K, Shi HL, He C. N⁶-methyladenosine modulates messenger RNA translation efficiency. Cell, 2015, 161(6): 1388-1399. doi: 10.1016/j.cell.2015.05.014
[19]	Shi HL, Wang X, Lu ZK, Zhao BS, Ma HH, Hsu PJ, Liu C, He C. YTHDF3 facilitates translation and decay of N⁶-methyladenosine-modified RNA. Cell Res, 2017, 27(3): 315-328. doi: 10.1038/cr.2017.15
[20]	Bi Z, Liu YH, Zhao YL, Yao YX, Wu RF, Liu Q, Wang YZ, Wang XX. A dynamic reversible RNA N⁶-methyladenosine modification: current status and perspectives. J Cell Physiol, 2019, 234(6): 7948-7956. doi: 10.1002/jcp.v234.6
[21]	Huang HL, Weng HY, Sun WJ, Qin X, Shi HL, Wu HZ, Zhao BS, Mesquita A, Liu C, Yuan CL, Hu YC, Hüttelmaier S, Skibbe JR, Su R, Deng XL, Dong L, Sun M, Li CY, Nachtergaele S, Wang YG, Hu C, Ferchen K, Greis KD, Jiang X, Wei MJ, Qu LH, Guan JL, He C, Yang JH, Chen JJ. Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol, 2018, 20(3): 285-295. doi: 10.1038/s41556-018-0045-z
[22]	Liu N, Dai Q, Zheng GQ, He C, Parisien M, Pan T. N⁶-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature, 2015, 518(7540): 560-564. doi: 10.1038/nature14234
[23]	Dai XX, Pi SB, Zhao LW, Wu YW, Shen JL, Zhang SY, Sha QQ, Fan HY. PABPN1 functions as a hub in the assembly of nuclear poly(A) domains that are essential for mouse oocyte development. Sci Adv, 2022, 8(43): eabn9016. doi: 10.1126/sciadv.abn9016
[24]	Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH. Stem cells. m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science, 2015, 347(6225): 1002-1006. doi: 10.1126/science.1261417 pmid: 25569111
[25]	Molinie B, Wang JK, Lim KS, Hillebrand R, Lu ZX, Van Wittenberghe N, Howard BD, Daneshvar K, Mullen AC, Dedon P, Xing Y, Giallourakis CC. m⁶A-LAIC-seq reveals the census and complexity of the m⁶A epitranscriptome. Nat Methods, 2016, 13(8): 692-698. doi: 10.1038/nmeth.3898 pmid: 27376769
[26]	Roundtree IA, Luo GZ, Zhang ZJ, Wang X, Zhou T, Cui YQ, Sha JH, Huang XX, Guerrero L, Xie P, He E, Shen B, He C. YTHDC1 mediates nuclear export of N⁶-methyladenosine methylated mRNAs. eLife, 2017, 6: e31311. doi: 10.7554/eLife.31311
[27]	Jiang JC, Zhang H, Cao LR, Dai XX, Zhao LW, Liu HB, Fan HY. Oocyte meiosis-coupled poly(A) polymerase α phosphorylation and activation trigger maternal mRNA translation in mice. Nucleic Acids Res, 2021, 49(10): 5867-5880. doi: 10.1093/nar/gkab431
[28]	Sha QQ, Dai XX, Dang Y, Tang F, Liu JP, Zhang YL, Fan HY. A MAPK cascade couples maternal mRNA translation and degradation to meiotic cell cycle progression in mouse oocytes. Development, 2017, 144(3): 452-463.
[29]	Dai XX, Jiang JC, Sha QQ, Jiang Y, Ou XH, Fan HY. A combinatorial code for mRNA 3'-UTR-mediated translational control in the mouse oocyte. Nucleic Acids Res, 2019, 47(1): 328-340. doi: 10.1093/nar/gky971
[30]	Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem, 2010, 79: 351-379. doi: 10.1146/annurev-biochem-060308-103103 pmid: 20533884
[31]	Lin SB, Choe J, Du P, Triboulet R, Gregory RI. The m⁶A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell, 2016, 62(3): 335-345. doi: 10.1016/j.molcel.2016.03.021
[32]	Jiang ZY, Fan HY. Five questions toward mRNA degradation in oocytes and preimplantation embryos: when, who, to whom, how, and why?†. Biol Reprod, 2022, 107(1): 62-75. doi: 10.1093/biolre/ioac014
[33]	Wang X, Lu ZK, Gomez A, Hon GC, Yue YN, Han DL, Fu Y, Parisien M, Dai Q, Jia GF, Ren B, Pan T, He C. N⁶-methyladenosine-dependent regulation of messenger RNA stability. Nature, 2014, 505(7481): 117-120. doi: 10.1038/nature12730
[34]	Liu JZ, Yue YN, Han DL, Wang X, Fu Y, Zhang L, Jia GF, Yu M, Lu ZK, Deng X, Dai Q, Chen WZ, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N⁶-adenosine methylation. Nat Chem Biol, 2014, 10(2): 93-95. doi: 10.1038/nchembio.1432
[35]	Pan ZX, Zhang JB, Li QF, Li YX, Shi FX, Xie Z, Liu HL. Current advances in epigenetic modification and alteration during mammalian ovarian folliculogenesis. J Genet Genomics, 2012, 39(3): 111-123. doi: 10.1016/j.jgg.2012.02.004 pmid: 22464470
[36]	边立华, 孟元光. 女性生殖系统发育异常的诊断与治疗. 中国妇产科临床杂志, 2017, 18(2): 182-183.
[37]	Overland MR, Li Y, Derpinghaus A, Aksel S, Cao M, Ladwig N, Cunha GR, Himelreich-Perić M, Baskin LS. Development of the human ovary: Fetal through pubertal ovarian morphology, folliculogenesis and expression of cellular differentiation markers. Differentiation, 2023, 129: 37-59. doi: 10.1016/j.diff.2022.10.005
[38]	Yao SJ, Lopez-Tello J, Sferruzzi-Perri AN. Developmental programming of the female reproductive system-a review. Biol Reprod, 2021, 104(4): 745-770. doi: 10.1093/biolre/ioaa232 pmid: 33354727
[39]	Cunha GR, Robboy SJ, Kurita T, Isaacson D, Shen J, Cao M, Baskin LS. Development of the human female reproductive tract. Differentiation, 2018, 103: 46-65. doi: S0301-4681(18)30100-2 pmid: 30236463
[40]	Wang HQ, Zhang JB, Zheng Y, Zhang WD, Guo HX, Cong S, Ding Y, Yuan B. Comprehensive analysis of differences in N⁶-methyladenosine RNA methylomes in the rat adenohypophysis after GnRH treatment. FASEB J, 2022, 36(3): e22204.
[41]	Magro-Lopez E, Muñoz-Fernández MÁ. The role of BMP signaling in female reproductive system development and function. Int J Mol Sci, 2021, 22(21): 11927. doi: 10.3390/ijms222111927
[42]	Gong YQ, Jiang QS, Liu LJ, Liao QY, Yu J, Xiang Z, Luo XG. METTL3-mediated m⁶A modification promotes processing and maturation of pri-miRNA-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion. Physiol Genomics, 2022, 54(9): 337-349. doi: 10.1152/physiolgenomics.00007.2022
[43]	Tatone C, Amicarelli F, Carbone MC, Monteleone P, Caserta D, Marci R, Artini PG, Piomboni P, Focarelli R. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update, 2008, 14(2): 131-142. doi: 10.1093/humupd/dmm048 pmid: 18239135
[44]	Amstislavsky SY, Brusentsev EY, Petrova OM, Naprimerov VA, Levinson AL. Development and aging of the mammalian reproductive system. Russ J Dev Biol, 2020, 51(1): 45-56. doi: 10.1134/S1062360420010075
[45]	Gougeon A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann Endocrinol (Paris), 2010, 71(3): 132-143. doi: 10.1016/j.ando.2010.02.021 pmid: 20362973
[46]	Liu CM, Ding LJ, Li JY, Dai JW, Sun HX. Advances in the study of ovarian dysfunction with aging. Hereditas (Beijing), 2019, 41(9): 816-826.
	刘传明, 丁利军, 李佳音, 戴建武, 孙海翔. 衰老导致卵巢功能低下研究进展. 遗传, 2019, 41(9): 816-826.
[47]	Rimon-Dahari N, Yerushalmi-Heinemann L, Alyagor L, Dekel N. Ovarian folliculogenesis. Results Probl Cell Differ, 2016, 58: 167-190. doi: 10.1007/978-3-319-31973-5_7 pmid: 27300179
[48]	Sun XF, Zhang JN, Jia Y, Shen W, Cao HG. Characterization of m⁶A in mouse ovary and testis. Clin Transl Med, 2020, 10(4): e141.
[49]	Xia H, Zhong CR, Wu XX, Chen J, Tao BB, Xia XQ, Shi MJ, Zhu ZY, Trudeau VL, Hu W. Mettl3 mutation disrupts gamete maturation and reduces fertility in zebrafish. Genetics, 2018, 208(2): 729-743. doi: 10.1534/genetics.117.300574 pmid: 29196300
[50]	Hu Y, Ouyang ZY, Sui XS, Qi MJ, Li MR, He YL, Cao YM, Cao QQ, Lu QN, Zhou S, Liu L, Liu L, Shen B, Shu WJ, Huo R. Oocyte competence is maintained by m⁶A methyltransferase KIAA1429-mediated RNA metabolism during mouse follicular development. Cell Death Differ, 2020, 27(8): 2468-2483. doi: 10.1038/s41418-020-0516-1
[51]	Zeng M, Dai X, Liang ZB, Sun RL, Huang S, Luo LP, Li ZX. Critical roles of mRNA m⁶A modification and YTHDC2 expression for meiotic initiation and progression in female germ cells. Gene, 2020, 753: 144810. doi: 10.1016/j.gene.2020.144810
[52]	Zhao XY, Tian GG, Fang Q, Pei XY, Wang ZX, Wu J. Comparison of RNA m⁶A and DNA methylation profiles between mouse female germline stem cells and STO cells. Mol Ther Nucleic Acids, 2020, 23: 431-439. doi: 10.1016/j.omtn.2020.11.020
[53]	Mu HY, Zhang T, Yang Y, Zhang DR, Gao J, Li JH, Yue L, Gao DF, Shi BB, Han Y, Zhong L, Chen XZ, Wang ZB, Lin Z, Tong MH, Sun QY, Yang YG, Han JY. METTL3- mediated mRNA N⁶-methyladenosine is required for oocyte and follicle development in mice. Cell Death Dis, 2021, 12(11): 989. doi: 10.1038/s41419-021-04272-9
[54]	Kasowitz SD, Ma J, Anderson SJ, Leu NA, Xu Y, Gregory BD, Schultz RM, Wang PJ. Nuclear m⁶A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet, 2018, 14(5): e1007412. doi: 10.1371/journal.pgen.1007412
[55]	Tadros W, Lipshitz HD. The maternal-to-zygotic transition: a play in two acts. Development, 2009, 136(18): 3033-3042. doi: 10.1242/dev.033183 pmid: 19700615
[56]	Sha QQ, Zhang J, Fan HY. A story of birth and death: mRNA translation and clearance at the onset of maternal- to-zygotic transition in mammals†. Biol Reprod, 2019, 101(3): 579-590. doi: 10.1093/biolre/ioz012
[57]	Sha QQ, Zhu YZ, Li S, Jiang Y, Chen L, Sun XH, Shen L, Ou XH, Fan HY. Characterization of zygotic genome activation-dependent maternal mRNA clearance in mouse. Nucleic Acids Res, 2020, 48(2): 879-894. doi: 10.1093/nar/gkz1111
[58]	Zhao BS, Wang X, Beadell AV, Lu ZK, Shi HL, Kuuspalu A, Ho RK, He C. m⁶A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature, 2017, 542(7642): 475-478. doi: 10.1038/nature21355
[59]	Ivanova I, Much C, Di Giacomo M, Azzi C, Morgan M, Moreira PN, Monahan J, Carrieri C, Enright AJ, O'Carroll D. The RNA m⁶A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol Cell, 2017, 67(6): 1059-1067.e4. doi: S1097-2765(17)30577-4 pmid: 28867294
[60]	Sha QQ, Zheng W, Wu YW, Li S, Guo L, Zhang SP, Lin G, Ou XH, Fan HY. Dynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans. Nat Commun, 2020, 11(1): 4917. doi: 10.1038/s41467-020-18680-6
[61]	West RC, Ming H, Logsdon DM, Sun JW, Rajput SK, Kile RA, Schoolcraft WB, Roberts RM, Krisher RL, Jiang ZL, Yuan Y. Dynamics of trophoblast differentiation in peri-implantation-stage human embryos. Proc Natl Acad Sci USA, 2019, 116(45): 22635-22644. doi: 10.1073/pnas.1911362116 pmid: 31636193
[62]	Qiu WY, Zhou YX, Wu HW, Lv XL, Yang LL, Ren ZX, Tian H, Yu QY, Li J, Lin WX, Zhao L, Luo SP, Gao J. RNA demethylase FTO mediated RNA m⁶A modification is involved in maintaining maternal-fetal interface in spontaneous abortion. Front Cell Dev Biol, 2021, 9: 617172. doi: 10.3389/fcell.2021.617172
[63]	Li XC, Jin F, Wang BY, Yin XJ, Hong W, Tian FJ. The m⁶A demethylase ALKBH5 controls trophoblast invasion at the maternal-fetal interface by regulating the stability of CYR61 mRNA. Theranostics, 2019, 9(13): 3853-3865. doi: 10.7150/thno.31868
[64]	Wu YW, Li S, Zheng W, Li YC, Chen L, Zhou Y, Deng ZQ, Lin G, Fan HY, Sha QQ. Dynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging. Nat Commun, 2022, 13(1): 3191. doi: 10.1038/s41467-022-30928-x
[65]	Liu C, Li LS, Yang B, Zhao YQ, Dong XY, Zhu LX, Ren XL, Huang B, Yue J, Jin L, Zhang HW, Wang L. Transcriptome-wide N⁶-methyladenine methylation in granulosa cells of women with decreased ovarian reserve. BMC Genomics, 2022, 23(1): 240. doi: 10.1186/s12864-022-08462-3
[66]	Zhang JJ, Chen Q, Du DF, Wu T, Wen JY, Wu M, Zhang Y, Yan W, Zhou S, Li Y, Jin Y, Luo AY, Wang SX. Can ovarian aging be delayed by pharmacological strategies? Aging (Albany NY), 2019, 11(2): 817-832.
[67]	Jiang ZX, Wang YN, Li ZY, Dai ZH, He Y, Chu K, Gu JY, Ji YX, Sun NX, Yang F, Li W. The m⁶A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging. Cell Death Dis, 2021, 12(8): 744. doi: 10.1038/s41419-021-04016-9
[68]	Ding CY, Zou QY, Ding J, Ling MF, Wang W, Li HX, Huang B. Increased N⁶-methyladenosine causes infertility is associated with FTO expression. J Cell Physiol, 2018, 233(9): 7055-7066. doi: 10.1002/jcp.v233.9
[69]	Huang BX, Ding CY, Zou QY, Wang W, Li H. Cyclophosphamide regulates N⁶-methyladenosine and m⁶A RNA enzyme levels in human granulosa cells and in ovaries of a premature ovarian aging mouse model. Front Endocrinol (Lausanne), 2019, 10: 415. doi: 10.3389/fendo.2019.00415
[70]	Zhu RG, Ji X, Wu X, Chen JJ, Li XS, Jiang H, Fu HP, Wang H, Lin Z, Tang X, Sun SX, Li QG, Wang BJ, Chen HS. Melatonin antagonizes ovarian aging via YTHDF2- MAPK-NF-κB pathway. Genes Dis, 2020, 9(2): 494-509.
[71]	Cooney LG, Lee I, Sammel MD, Dokras A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod, 2017, 32(5): 1075-1091. doi: 10.1093/humrep/dex044
[72]	Zhang S, Deng WL, Liu QY, Wang PY, Yang W, Ni WH. Altered m6 A modification is involved in up-regulated expression of FOXO3 in luteinized granulosa cells of non-obese polycystic ovary syndrome patients. J Cell Mol Med, 2020, 24(20): 11874-11882. doi: 10.1111/jcmm.v24.20
[73]	Zhou L, Han X, Li W, Wang N, Yao L, Zhao YH, Zhang LQ. N⁶-methyladenosine demethylase FTO induces the dysfunctions of ovarian granulosa cells by upregulating flotillin 2. Reprod Sci, 2022, 29(4): 1305-1315. doi: 10.1007/s43032-021-00664-6
[74]	Li XO, Xiong WQ, Long XF, Dai X, Peng Y, Xu Y, Zhang ZB, Zhang L, Liu Y. Inhibition of METTL3/m⁶A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosis†. Biol Reprod, 2021, 105(5): 1221-1233. doi: 10.1093/biolre/ioab152 pmid: 34382070
[75]	Jiang L, Zhang MM, Wu JN, Wang SX, Yang X, Yi MY, Zhang XY, Fang XL. Exploring diagnostic m⁶A regulators in endometriosis. Aging (Albany NY), 2020, 12(24): 25916-25938.
[76]	Zhai JY, Li S, Sen S, Opoku-Anane J, Du YZ, Chen ZJ, Giudice LC. m⁶A RNA methylation regulators contribute to eutopic endometrium and myometrium dysfunction in adenomyosis. Front Genet, 2020, 11: 716. doi: 10.3389/fgene.2020.00716
[77]	Gu Y, Chu XD, Morgan JA, Lewis DF, Wang YP. Upregulation of METTL3 expression and m⁶A RNA methylation in placental trophoblasts in preeclampsia. Placenta, 2021, 103:43-49. doi: 10.1016/j.placenta.2020.10.016 pmid: 33070036
[78]	Guo YP, Song WX, Yang YL. Inhibition of ALKBH5- mediated m⁶A modification of PPARG mRNA alleviates H/R-induced oxidative stress and apoptosis in placenta trophoblast. Environ Toxicol, 2022, 37(4): 910-924. doi: 10.1002/tox.v37.4
[79]	Chen JY, Fang YW, Xu Y, Sun HT. Role of m⁶A modification in female infertility and reproductive system diseases. Int J Biol Sci, 2022, 18(9): 3592-3604. doi: 10.7150/ijbs.69771 pmid: 35813486
[80]	Huang H, Wang YN, Kandpal M, Zhao GY, Cardenas H, Ji YR, Chaparala A, Tanner EJ, Chen JJ, Davuluri RV, Matei D. FTO-dependent N⁶-methyladenosine modifications inhibit ovarian cancer stem cell self-renewal by blocking cAMP signaling. Cancer Res, 2020, 80(16): 3200-3214. doi: 10.1158/0008-5472.CAN-19-4044 pmid: 32606006
[81]	Wu SQ, Liu KT, Zhou BY, Wu SW. N⁶-methyladenosine modifications in maternal-fetal crosstalk and gestational diseases. Front Cell Dev Biol, 2023, 11: 1164706. doi: 10.3389/fcell.2023.1164706
[82]	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): 1635-1646. doi: 10.1016/j.cell.2012.05.003 pmid: 22608085
[83]	Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq. Nature, 2012, 485(7397): 201-206. doi: 10.1038/nature11112
[84]	Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE, Jaffrey SR. Single-nucleotide-resolution mapping of m⁶A and m⁶Am throughout the transcriptome. Nat Methods, 2015, 12(8): 767-772. doi: 10.1038/nmeth.3453 pmid: 26121403
[85]	Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, Vågbø CB, Kusśnierczyk A, Klungland A, Darnell JE Jr, Darnell RB. A majority of m⁶A residues are in the last exons, allowing the potential for 3' UTR regulation. Genes Dev, 2015, 29(19): 2037-2053. doi: 10.1101/gad.269415.115
[86]	Garcia-Campos MA, Edelheit S, Toth U, Safra M, Shachar R, Viukov S, Winkler R, Nir R, Lasman L, Brandis A, Hanna JH, Rossmanith W, Schwartz S. deciphering the "m⁶A code" via antibody-independent quantitative profiling. Cell, 2019, 178(3): 731-747.e16. doi: S0092-8674(19)30676-2 pmid: 31257032
[87]	Zhang Z, Chen LQ, Zhao YL, Yang CG, Roundtree IA, Zhang ZJ, Ren J, Xie W, He C, Luo GZ. Single-base mapping of m⁶A by an antibody-independent method. Sci Adv, 2019, 5(7): eaax0250. doi: 10.1126/sciadv.aax0250
[88]	Shu X, Cao J, Cheng MH, Xiang SY, Gao MS, Li T, Ying XE, Wang FQ, Yue YN, Lu ZK, Dai Q, Cui XL, Ma LJ, Wang YZ, He C, Feng XH, Liu JZ. A metabolic labeling method detects m⁶A transcriptome-wide at single base resolution. Nat Chem Biol, 2020, 16(8): 887-895. doi: 10.1038/s41589-020-0526-9
[89]	Meyer KD. DART-seq: an antibody-free method for global m⁶A detection. Nat Methods, 2019, 16(12): 1275-1280. doi: 10.1038/s41592-019-0570-0 pmid: 31548708
[90]	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): 191-198. doi: 10.1038/ncb2902 pmid: 24394384
[91]	Nagarajan A, Janostiak R, Wajapeyee N. Dot blot analysis for measuring global N⁶-methyladenosine modification of RNA. Methods Mol Biol, 2019, 1870: 263-271.
[92]	Thüring K, Schmid K, Keller P, Helm M. LC-MS analysis of methylated RNA. Methods Mol Biol, 2017, 1562: 3-18. doi: 10.1007/978-1-4939-6807-7_1 pmid: 28349450
[93]	Feng JX, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using MACS. Nat Protoc, 2012, 7(9): 1728-1740. doi: 10.1038/nprot.2012.101 pmid: 22936215
[94]	Meng J, Cui XD, Rao MK, Chen YD, Huang YF. Exome-based analysis for RNA epigenome sequencing data. Bioinformatics, 2013, 29(12): 1565-1567. doi: 10.1093/bioinformatics/btt171 pmid: 23589649
[95]	Yang Y, Chen YS, Sun BF, Yang YG. RNA methylation: regulations and mechanisms. Hereditas(Beijing), 2018, 40(11): 964-976.
	杨莹, 陈宇晟, 孙宝发, 杨运桂. RNA甲基化修饰调控和规律. 遗传, 2018, 40(11): 964-976.
[96]	Li JX, Chen ZJ, Chen F, Xie GY, Ling YY, Peng YX, Lin Y, Luo N, Chiang CM, Wang HS. Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein. Nucleic Acids Res, 2020, 48(10): 5684-5694. doi: 10.1093/nar/gkaa269 pmid: 32356894

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类型	调控因子	功能
写入器(writers)	METTL3	催化m⁶A甲基化；调控RNA代谢
	METTL14	MTC关键组分，协助底物识别
	WTAP	MTC重要辅因子，辅助核定位
	VIRMA(KIAA1429)	MTC重要辅因子，增强底物结合能力
擦除器(erasers)	FTO	m⁶A甲基化去除，调控可变剪接及翻译效率
擦除器(erasers)	ALKBH5	m⁶A甲基化去除，调控RNA出核转运
阅读器(readers)	YTHDC1	调控可变剪接及RNA出核转运
	YTHDC2	增强mRNA翻译效率；促进mRNA衰变
	YTHDF1	翻译起始调控；提高翻译效率
	YTHDF2	降低RNA稳定性，促进RNA衰变
	YTHDF3	辅助调控mRNA翻译和衰变
	hnRNPC/hnRNPA2B1	可变剪接调控；RNA结构开关
	IGF2BP1/2/3	增强RNA稳定性；mRNA翻译调控

发育、衰老过程或疾病类型	m⁶A修饰调控因子	方式
卵泡发育	METTL3/14	表达上调促进m⁶A水平增加
	FTO	表达下调促进m⁶A水平增加
	KIAA1429	缺失将抑制颗粒细胞增殖并促进凋亡
	YTHDC2	缺失将导致性腺显着变小
卵母细胞成熟	METTL3	METTL3突变将会导致性腺减小，减数分裂停滞，阻断卵母细胞成熟
卵母细胞成熟	YTHDC1	调节卵母细胞RNA剪接和可变多聚腺苷酸化
母体到合子转换和早期胚胎发育	KIAA1429	缺失导致异常可变剪接，减数分裂停滞
	YTHDC2	敲低将减缓母体mRNA的降解，导致早期胚胎发育缺陷
	METTL3	敲低干扰母体mRNA的降解
卵巢衰老	FTO	FTO下调改变mRNA的稳定性，诱导卵巢衰老
卵巢衰老	YTHDF2	抑制YTHDF2调控通路有助于保护卵巢上皮细胞
原发性卵巢功能不全	FTO	FTO表达的降低是POI的高风险因素
多囊卵巢综合征	METTL3/14和FTO/ALKBH5	调控机制异常
子宫内膜异位和子宫肌腺病	METTL3	敲低促进人子宫内膜基质细胞的迁移和侵袭
子宫内膜异位和子宫肌腺病	hnRNPA2B1和hnRNPC	免疫应答相关
先兆子痫	METTL3	阻碍滋养层的迁移和侵袭
先兆子痫	ALKBH5	缓解疾病进展
自然流产和复发性流产	FTO	改变免疫耐受和血管生成
自然流产和复发性流产	YTHDF2	敲低增强滋养层细胞侵袭
卵巢癌	METTL3	促进癌细胞生长和侵袭
	YTHDF1/2/3	促进扩散和迁移，影响病理分级和预后
	FTO	抑制体内肿瘤发生
	ALKBH5	参与肿瘤发生
宫颈癌	METTL3	促进癌细胞增殖和侵袭
宫颈癌	FTO	促进癌细胞增殖和迁移，增强耐药性
子宫内膜癌	METTL3	促进肿瘤的增殖和致癌性
	FTO	促进癌细胞转移
	ALKBH5	促进肿瘤的增殖和致癌性
	WTAP	促进癌症进展
	YTHDF2	抑制肿瘤细胞致癌性

名称	RNA类型	技术手段	分辨率	耗时	定量	灵敏度	参考文献
MeRIP-seq	mRNA lncRNA	m⁶A抗体沉淀高通量测序	100~200 bp	长	非定量	中	[82]
m⁶A-seq	mRNA lncRNA	m⁶A抗体沉淀高通量测序	100~200 bp	长	非定量	中	[83]
miCLIP	ployA RNA	m⁶A抗体沉淀光交联高通量测序	1 bp	长	非定量	高	[84]
m⁶A-CLIP	ployA RNA	m⁶A抗体沉淀光交联高通量测序	1 bp	长	非定量	高	[85]
MAZTER-seq	ployA RNA	MazF降解定量逆转录PCR 或高通量测序	1 bp (仅ACA motif)	中	定量	高 (仅ACA motif)	[86]
m⁶A-REF-seq	ployA RNA	MazF、FTO降解高通量测序	1 bp (仅ACA motif)	中	定量	高 (仅ACA motif)	[87]
m⁶A-label-seq	mRNA	代谢标记高通量测序	1 bp	长	非定量	中	[88]
DART-seq	ployA RNA	基因编辑细胞转染高通量测序	10 bp	长	非定量	低	[89]
MeRIP-qPCR	ployA RNA	m⁶A抗体沉淀定量逆转录PCR	100~200 bp	短	半定量	中	[90]
m⁶A dot blot	mRNA	斑点杂交	无	短	半定量	中	[91]
LC-MS	mRNA totalRNA	液相色谱质谱	无	中	定量	高	[92]

Effects of N⁶-methyladenosine modification on the function of the female reproductive system

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