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蒋婷, 张学广, 许文明. N6-甲基腺嘌呤修饰及其调控因子在男性生殖中的作用[J]. koko体育app 学报(医学版), 2024, 55(3): 527-534. DOI:
引用本文: 蒋婷, 张学广, 许文明. N6-甲基腺嘌呤修饰及其调控因子在男性生殖中的作用[J]. koko体育app 学报(医学版), 2024, 55(3): 527-534. DOI:
JIANG Ting, ZHANG Xueguang, XU Wenming. The Roles of N6-Methyladenosine Modification and Its Regulators in Male Reproduction[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(3): 527-534. DOI:
Citation: JIANG Ting, ZHANG Xueguang, XU Wenming. The Roles of N6-Methyladenosine Modification and Its Regulators in Male Reproduction[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(3): 527-534. D🦄OI:

N6-甲基腺嘌呤修饰及其调控因子在男性生殖中的作用

The Roles of N6-Methyladenosine Modification and Its Regulators in Male Reproduction

  • 摘要: 在哺乳动物中,精子发生是一个高度复杂且协调的生殖细胞分化过程,这一过程受到转录、转录后和翻译水平的精确调控,以确保不同发育阶段的生精细胞正确表达特定基因并维持正常的生精过程。N6-甲基腺嘌呤(N6-methyladenosine, m6A)是真核生物mRNA上最丰富的修饰,在诸如mRNA剪接、转运和翻译等多个生物过程发挥关键作用。RNA甲基化修饰是一个动态可逆的过程,主要通过编码器(writers)催化、消码器(erasers)去除和读码器(readers)识别来调控修饰水平。本文首先概述了精子发生的主要阶段,然后重点介绍m6A修饰及相关蛋白在雄性生殖细胞不同发育阶段的关键功能,最后简要总结了目前检测m6A的主要方法,以期深入了解RNA修饰在调控精子发生以及在男性不育中发挥的作用和机制。  
    Abstract: Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with infertility exhibit symptoms such as oligospermia, asthenospermia, azoospermia, and compromised sperm quality. Spermatogenesis is a complex and tightly coordinated process of germ cell differentiation, precisely regulated at transcriptional, posttranscriptional, and translational levels to ensure stage-specific gene expression during the development of spermatogenic cells and normal spermiogenesis. N6-methyladenosine (m6A) stands out as the most prevalent modification on eukaryotic mRNA, playing pivotal roles in various biological processes, including mRNA splicing, transportation, and translation. RNA methylation modification is a dynamic and reversible process primarily mediated by “writers”, removed by “erasers”, and recognized by “readers”. In mammals, the aberrant methylation modification of m6A on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted m6A modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of m6A regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of m6A regulatory proteins have been detected in anomalous human semen samples, including those of oligospermia, asthenozoospermia, and azoospermia. Furthermore, the examination of both sperm samples and testicular tissues revealed abnormal mRNA m6A modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of m6A modification might serve as an integral link in the mechanism of male infertility. This paper presents a comprehensive review of the recent discoveries regarding the spatial and temporal expression dynamics of m6A regulators in testicular tissues and the correlation between deregulated m6A regulators and human male infertility. Previous studies predominantly utilized constitutive or conditional knockout animal models for testicular phenotypic investigations. However, gene suppression in additional tissues could potentially influence the testis in constitutive knockout models. Furthermore, considering the compromised spermatogenesis observed in constitutive animals, distinguishing between the indirect effects of gene depletion on testicular development and its direct impact on the spermatogenic process is challenging, due to their intricate relationship. Such confounding factors might compromise the validity of the findings. To address this challenge, an inducible and conditional gene knockout model may serve as a superior approach. To date, nearly all reported studies have concentrated solely on the level changes of m6A and its regulators in germs cells, while the understanding of the function of m6A modification in testicular somatic cells remains limited. Testicular somatic cells, including peritubular myoid cells, Sertoli cells, and Leydig cells, play indispensable roles during spermatogenesis. Hence, comprehensive exploration of m6A modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or m6A regulatory factors within the testes is warranted. To elucidate the role of m6A modification in germ cells and testicular somatic cells, detailed experimental strategies need to be implemented. Among them, manipulation of the levels of key enzymes involved in m6A methylation and demethylation might be the most effective approach. Moreover, comprehensive analysis of the gene expression profiles involved in various signaling pathways, such as Wnt/β-catenin, Ras/MAPK, and Hippo, in m6A-modified germ cells and testicular somatic cells can provide more insight into its regulatory role in the spermatogenesis process. Further research in this area could provide valuable insights for developing innovative strategies to treat male infertility. Finally, considering the mitigation impact of m6A imbalance regulation on disease, investigation concerning whether restoring the equilibrium of m6A modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of m6A modulation in male infertility.  

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