Advances in research on RNA N-6-methyladenosine(m6A) modification related enzymes in mammalian spermatogenesis

doi:10.16352/j.issn.1001-6325.2023.04.0524

Abstract

Abstract: N-6-methyladenosine(m6A) has been well-known to be a type of RNA epigenetic modification over the past decade. The m6A modification enzymes include “Writers” (METTL3/14/WTAP, etc.),“Erasers” (FTO and ALKBH5) and “Readers” (YTHDC1/2,YTHDF1/2/3, etc.), which mediate RNA methylation, demethylation, and recognition binding via a synergistic regulatory system, thereby regulating the fate of RNA after transcription. Spermatogenesis is an essential process of sexual maturation and maintenance of fertility in male mammals, involving the proliferation, and differentiation of Sertoli cells, Leydig cells and spermatogonia, and maintenance of spermatogenic microenvironment. More recently, there are some researches showed that the m6A regulatory system was involved in mammalian spermatogenesis. Abnormal m6A modification and imbalances in the m6A regulatory system can lead to abnormal testicular development, abnormal spermatogenesis and male infertility. This review summarizes the function of m6A modification enzymes in spermatogenesis, and further analyzes the role of m6A differentially modified transcripts in normal spermatogenesis, which has a great significance for understanding mammalian spermatogenesis and decoding the molecular mechanism of clinical spermatogenesis disorders.

Key words: m6A modification, spermatogenesis, Sertoli cell, Leydig cell, spermatogenic cell

CLC Number:

ZHANG Qiang, SU Wenhui. Advances in research on RNA N-6-methyladenosine(m6A) modification related enzymes in mammalian spermatogenesis[J]. Basic & Clinical Medicine, 2023, 43(4): 524-531.

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URL: http://journal11.magtechjournal.com/Jwk_jcyxylc/EN/10.16352/j.issn.1001-6325.2023.04.0524

http://journal11.magtechjournal.com/Jwk_jcyxylc/EN/Y2023/V43/I4/524

References

[1]Cole LA. Human male spermatogenesis[M]//Cole LA. Biology of life. Online; Academic Press, 2016: 135-141.
[2]Roundtree IA, Evans ME, Pan T, et al. Dynamic rna modifications in gene expression regulation[J]. Cell, 2017, 169: 1187-1200.
[3]Boccaletto P, Baginski B. Modomics: An operational guide to the use of the rna modification pathways database[J]. Methods Mol Biol, 2021, 2284: 481-505.
[4]Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger rna from novikoff hepatoma cells[J]. Proc Natl Acad Sci U S A, 1974, 71: 3971-3975.
[5]Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear rna is a major substrate of the obesity-associated fto[J]. Nat Chem Biol, 2011, 7: 885-887.
[6]Lin Z, Hsu PJ, Xing X, et al. Mettl3-/mettl14-mediated mrna n(6)-methyladenosine modulates murine spermatogenesis[J]. Cell Res, 2017, 27: 1216-1230.
[7]Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of mettl3 and mettl14 methyltransferases[J]. Mol Cell, 2016, 63: 306-317.
[8]Xiao W, Adhikari S, Dahal U, et al. Nuclear m6a reader ythdc1 regulates mrna splicing[J]. Mol Cell, 2016, 61: 507-519.
[9]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: 177-189.
[10]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: 1635-1646.
[11]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: 201-206.
[12]Yue Y, Liu J, Cui X, et al. Virma mediates preferential m(6)a mrna methylation in 3'utr and near stop codon and associates with alternative polyadenylation[J]. Cell Discov, 2018, 4: 10.
[13]Ruan H, Yang F, Deng L, et al. Human m(6)a-mrna and lncrna epitranscriptomic microarray reveal function of rna methylation in hemoglobin h-constant spring disease[J]. Sci Rep, 2021, 11: 20478.
[14]Patil DP, Chen CK, Pickering BF, et al. M(6)a rna methylation promotes xist-mediated transcriptional repression[J]. Nature, 2016, 537: 369-373.
[15]Zheng GQ, Dahl JA, Niu YM, et al. Alkbh5 is a mammalian rna demethylase that impacts rna metabolism and mouse fertility[J]. Mol Cell, 2013, 49: 18-29.
[16]Mauer J, Sindelar M, Despic V, et al. Fto controls reversible m(6)am rna methylation during snrna biogenesis[J]. Nat Chem Biol, 2019, 15: 340-347.
[17]Roundtree IA, Luo GZ, Zhang Z, et al. Ythdc1 mediates nuclear export of n(6)-methyladenosine methylated mrnas[J]. Elife, 2017, 6. e31311.doi: 10.7554/eLife.31311.
[18]Hsu PJ, Zhu Y, Ma H, et al. Ythdc2 is an n(6)-methyladenosine binding protein that regulates mammalian spermatogenesis[J]. Cell Res, 2017, 27: 1115-1127.
[19]Wang X, Zhao BS, Roundtree IA, et al. N(6)-methyladenosine modulates messenger rna translation efficiency[J]. Cell, 2015, 161: 1388-1399.
[20]Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger rna stability[J]. Nature, 2014, 505: 117-120.
[21]Shi H, Wang X, Lu Z, et al. Ythdf3 facilitates translation and decay of n(6)-methyladenosine-modified rna[J]. Cell Res, 2017, 27: 315-328.
[22]Li A, Chen YS, Ping XL, et al. Cytoplasmic m(6)a reader ythdf3 promotes mrna translation[J]. Cell Res, 2017, 27: 444-447.
[23]Huang H, Weng H, Sun W, et al. Recognition of rna n(6)-methyladenosine by igf2bp proteins enhances mrna stability and translation[J]. Nat Cell Biol, 2018, 20: 285-295.
[24]Meyer KD, Patil DP, Zhou J, et al. 5' utr m(6)a promotes cap-independent translation[J]. Cell, 2015, 163: 999-1010.
[25]Alarcon CR, Goodarzi H, Lee H, et al. Hnrnpa2b1 is a mediator of m(6)a-dependent nuclear rna processing events[J]. Cell, 2015, 162: 1299-1308.
[26]Liu N, Dai Q, Zheng G, et al. N(6)-methyladenosine-dependent rna structural switches regulate rna-protein interactions[J]. Nature, 2015, 518: 560-564.
[27]Liu N, Zhou KI, Parisien M, et al. N6-methyladenosine alters rna structure to regulate binding of a low-complexity protein[J]. Nucleic Acids Res, 2017, 45: 6051-6063.
[28]Fu Y, Dominissini D, Rechavi G, et al. Gene expression regulation mediated through reversible m6a rna methylation[J]. Nat Rev Genet, 2014, 15: 293-306.
[29]Bi Z, Liu Y, Zhao Y, et al. A dynamic reversible rna n(6) -methyladenosine modification: Current status and perspectives[J]. J Cell Physiol, 2019, 234: 7948-7956.
[30]Cao G, Li HB, Yin Z, et al. Recent advances in dynamic m6a rna modification[J]. Open Biol, 2016, 6: 160003.
[31]Shi H, Wei J, He C. Where, when, and how: Context-dependent functions of rna methylation writers, readers, and erasers[J]. Mol Cell, 2019, 74: 640-650.
[32]Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mrna methylation[J]. Nat Rev Mol Cell Biol, 2019, 20: 608-624.
[33]Adhikari S, Xiao W, Zhao YL, et al. M(6)a: Signaling for mrna splicing[J]. RNA Biol, 2016, 13: 756-759.
[34]Lesbirel S, Wilson SA. The m(6)amethylase complex and mrna export[J]. Biochim Biophys Acta Gene Regul Mech, 2019, 1862: 319-328.
[35]Frye M, Harada BT, Behm M, et al. Rna modifications modulate gene expression during development[J]. Science, 2018, 361: 1346-1349.
[36]Lukassen S, Bosch E, Ekici AB, et al. Characterization of germ cell differentiation in the male mouse through single-cell rna sequencing[J]. Sci Rep, 2018, 8: 6521.
[37]Kalucka J, de Rooij L, Goveia J, et al. Single-cell transcriptome atlas of murine endothelial cells[J]. Cell, 2020, 180: 764-779 e720.
[38]Yu XW, Li TT, Du XM, et al. Single-cell rna sequencing reveals atlas of dairy goat testis cells[J]. Zool Res, 2021, 42: 401-405.
[39]Wu Y, Guo T, Li J, et al. The transcriptional cell atlas of testis development in sheep at pre-sexual maturity[J]. Curr Issues Mol Biol, 2022, 44: 483-497.
[40]Yang H, Ma J, Wan Z, et al. Characterization of sheep spermatogenesis through single-cell rna sequencing[J]. FASEB J, 2021, 35: e21187.
[41]Zhang L, Li F, Lei P, et al. Single-cell rna-sequencing reveals the dynamic process and novel markers in porcine spermatogenesis[J]. J Anim Sci Biotechnol, 2021, 12: 122.
[42]Zhang L, Guo M, Liu Z, et al. Single-cell rna-seq analysis of testicular somatic cell development in pigs[J]. J Genet Genomics, 2022,49:1016-1028.
[43]Lau X, Munusamy P, Ng MJ, et al. Single-cell rna sequencing of the cynomolgus macaque testis reveals conserved transcriptional profiles during mammalian spermatogenesis[J]. Dev Cell, 2020, 54: 548-566 e547.
[44]Wang M, Liu X, Chang G, et al. Single-cell rna sequencing analysis reveals sequential cell fate transition during human spermatogenesis[J]. Cell Stem Cell, 2018, 23: 599-614 e594.
[45]Sun X, Zhang J, Jia Y, et al. Characterization of m6a in mouse ovary and testis[J]. Clin Transl Med, 2020, 10: e141.
[46]Zhao X, Lin Z, Fan Y, et al. Ythdf2 is essential for spermatogenesis and fertility by mediating a wave of transcriptional transition in spermatogenic cells[J]. Acta Biochim Biophys Sin (Shanghai), 2021, 53: 1702-1712.
[47]Chen Y, Wang J, Xu D, et al. M(6)a mrna methylation regulates testosterone synthesis through modulating autophagy in leydig cells[J]. Autophagy, 2021, 17: 457-475.
[48]Liu SH, Ma XY, Yue TT, et al. Transcriptome-wide m6a analysis provides novel insights into testicular development and spermatogenesis in xia-nan cattle[J]. Front Cell Dev Biol, 2021, 9: 791221.
[49]Liu Z, Chen X, Zhang P, et al. Transcriptome-wide dynamics of m(6)a mrna methylation during porcine spermatogenesis[J]. Genomics Proteomics Bioinformatics, 2021, S1672-0229(21)00181-9. doi: 10.1016/j.gpb.2021.08.006.
[50]Zhao TX, Wang JK, Shen LJ, et al. Increased m6a rna modification is related to the inhibition of the nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury[J]. Environ Pollut, 2020, 259: 113911.
[51]Soumillon M, Necsulea A, Weier M, et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis[J]. Cell Rep, 2013, 3: 2179-2190.
[52]Yu Y, Fuscoe JC, Zhao C, et al. A rat rna-seq transcriptomic bodymap across 11 organs and 4 developmental stages[J]. Nat Commun, 2014, 5: 3230.
[53]Zimmermann C, Stevant I, Borel C, et al. Research resource: The dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis[J]. Mol Endocrinol, 2015, 29: 627-642.
[54]Schwartz S, Agarwala Sudeep D, Mumbach Maxwell R, et al. High-resolution mapping reveals a conserved, widespread, dynamic mrna methylation program in yeast meiosis[J]. Cell, 2013, 155: 1409-1421.
[55]Xu K, Yang Y, Feng GH, et al. Mettl3-mediated m(6)a regulates spermatogonial differentiation and meiosis initiation[J]. Cell Res, 2017, 27: 1100-1114.
[56]Lasman L, Krupalnik V, Viukov S, et al. Context-dependent functional compensation between ythdf m(6)a reader proteins[J]. Genes Dev, 2020, 34: 1373-1391.
[57]Jia GX, Lin Z, Yan RG, et al. Wtap function in sertoli cells is essential for sustaining the spermatogonial stem cell niche[J]. Stem Cell Reports, 2020, 15: 968-982.
[58]Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits fto demethylation of m6a over alkbh5[J]. Nucleic Acids Res, 2015, 43: 373-384.
[59]Huang T, Guo J, Lv Y, et al. Meclofenamic acid represses spermatogonial proliferation through modulating m(6)a rna modification[J]. J Anim Sci Biotechnol, 2019, 10: 63.
[60]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[J]. Proc Natl Acad Sci U S A, 2018, 115: E325-E333.
[61]Hong S, Shen X, Luo C, et al. Comparative analysis of the testes from wild-type and alkbh5-knockout mice using single-cell rna sequencing[J]. G3 (Bethesda), 2022, 12:jkac130. doi: 10.1093/g3journal/jkac130
[62]Cheng CY, Mruk DD. The blood-testis barrier and its implications for male contraception[J]. Pharmacol Rev, 2012, 64: 16-64.
[63]Kasowitz SD, Ma J, Anderson SJ, et al. Nuclear m6a reader ythdc1 regulates alternative polyadenylation and splicing during mouse oocyte development[J]. PLoS Genet, 2018, 14: e1007412.
[64]Roundtree IA, He C. Nuclear m6a reader ythdc1 regulates mrna splicing[J]. Trends Genet, 2016, 32: 320-321.
[65]Wojtas MN, Pandey RR, Mendel M, et al. Regulation of m(6)a transcripts by the 3′--＞5′ rna helicase ythdc2 is essential for a successful meiotic program in the mammalian germline[J]. Mol Cell, 2017, 68: 374-387 e312.
[66]Jain D, Puno MR, Meydan C, et al. Ketu mutant mice uncover an essential meiotic function for the ancient rna helicase ythdc2[J]. Elife, 2018, 7:e30919. doi: 10.7554/eLife.30919
[67]Bai G, Zhai X, Liu L, et al. The molecular charac-teristics in different procedures of spermatogenesis[J]. Gene, 2022, 826: 146405.
[68]Tang Z, Li C, Kang B, et al. Gepia: A web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45: W98-W102.
[69]Yang Y, Huang W, Huang JT, et al. Increased n6-methyladenosine in human sperm rna as a risk factor for asthenozoospermia[J]. Sci Rep, 2016, 6: 24345.
[70]Glazer CH, Bonde JP, Giwercman A, et al. Risk of diabetes according to male factor infertility: A register-based cohort study[J]. Hum Reprod, 2017, 32: 1474-1481.
[71]Chen X, Lin Q, Wen J, et al. Whole genome bisulfite sequencing of human spermatozoa reveals differentially methylated patterns from type 2 diabetic patients[J]. J Diabetes Investig, 2020, 11: 856-864.
[72]Landfors M, Nakken S, Fusser M, et al. Sequencing of fto and alkbh5 in men undergoing infertility work-up identifies an infertility-associated variant and two missense mutations[J]. Fertil Steril, 2016, 105: 1170-1179.e1175.