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

Q3 Medicine 四川大学学报(医学版) Pub Date : 2024-05-20 DOI:10.12182/20240560103
Ting Jiang, Xueguang Zhang, Wenming Xu
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N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted m<sup>6</sup>A modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of m<sup>6</sup>A regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of m<sup>6</sup>A 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 m<sup>6</sup>A modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of m<sup>6</sup>A 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 m<sup>6</sup>A regulators in testicular tissues and the correlation between deregulated m<sup>6</sup>A 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 m<sup>6</sup>A and its regulators in germs cells, while the understanding of the function of m<sup>6</sup>A 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 m<sup>6</sup>A modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or m<sup>6</sup>A regulatory factors within the testes is warranted. To elucidate the role of m<sup>6</sup>A 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 m<sup>6</sup>A 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 m<sup>6</sup>A-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 m<sup>6</sup>A imbalance regulation on disease, investigation concerning whether restoring the equilibrium of m<sup>6</sup>A modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of m<sup>6</sup>A modulation in male infertility.</p>","PeriodicalId":39321,"journal":{"name":"四川大学学报(医学版)","volume":"55 3","pages":"527-534"},"PeriodicalIF":0.0000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211765/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"四川大学学报(医学版)","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.12182/20240560103","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

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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[N6-甲基腺苷修饰及其调节因子在男性生殖中的作用]。
据估计,全世界有 10%至 15%的夫妇患有不孕不育症,其中约有一半的病例与男性问题有关。大多数被诊断出患有不育症的男性会表现出少精症、无精症、无精子症和精子质量下降等症状。精子发生是一个复杂而紧密协调的生殖细胞分化过程,在转录、转录后和翻译水平上受到精确调控,以确保生精细胞发育和正常精子发生过程中特定阶段的基因表达。N6-甲基腺苷(m6A)是真核 mRNA 上最常见的修饰,在 mRNA 剪接、运输和翻译等各种生物过程中发挥着关键作用。RNA 甲基化修饰是一个动态、可逆的过程,主要由 "书写者 "介导,"擦除者 "去除,"阅读者 "识别。在哺乳动物中,mRNA 上 m6A 的异常甲基化修饰与包括男性不育在内的多种疾病有关。然而,m6A 修饰紊乱与人类男性不育症发病机制的确切关系仍未解决。耐人寻味的是,m6A调节因子在睾丸中的表达水平与精子浓度、活力和形态的严重程度之间存在着明显的相关性。在异常人类精液样本中,包括少精子症、无精子症和无精子症样本中,发现了 m6A 调节蛋白的异常表达模式。此外,精子样本和睾丸组织的检查均发现 mRNA m6A 修饰异常,导致不育男性精子活力和浓度降低。因此,我们推测 m6A 修饰失调可能是男性不育机制中不可或缺的一环。本文全面综述了有关 m6A 调节因子在睾丸组织中的时空表达动态的最新发现,以及失调的 m6A 调节因子与人类男性不育之间的相关性。以往的研究主要利用组成型或条件性基因敲除动物模型进行睾丸表型研究。然而,在组成型基因敲除模型中,其他组织的基因抑制可能会对睾丸产生潜在影响。此外,考虑到在组成型动物中观察到的精子发生受到影响,区分基因耗竭对睾丸发育的间接影响和对精子发生过程的直接影响具有挑战性,因为它们之间的关系错综复杂。这些干扰因素可能会影响研究结果的有效性。为了应对这一挑战,诱导性和条件性基因敲除模型可能是一种更好的方法。迄今为止,几乎所有报道的研究都只集中于胚芽细胞中 m6A 及其调节因子的水平变化,而对睾丸体细胞中 m6A 修饰功能的了解仍然有限。睾丸体细胞包括管周肌细胞、Sertoli细胞和Leydig细胞,在精子发生过程中发挥着不可或缺的作用。因此,有必要对这些细胞内的 m6A 修饰进行全面探索,将其作为另一种重要的调控机制。此外,还需要探索睾丸内是否存在独特的甲基化机制或 m6A 调节因子。要阐明m6A修饰在生殖细胞和睾丸体细胞中的作用,需要实施详细的实验策略。其中,操纵参与 m6A 甲基化和去甲基化的关键酶的水平可能是最有效的方法。此外,对m6A修饰的生殖细胞和睾丸体细胞中涉及Wnt/β-catenin、Ras/MAPK和Hippo等多种信号通路的基因表达谱进行全面分析,可以更深入地了解m6A在精子发生过程中的调控作用。这方面的进一步研究可为开发治疗男性不育症的创新策略提供有价值的见解。最后,考虑到m6A失衡调控对疾病的缓解作用,研究恢复m6A修饰调控的平衡是否能恢复正常的生精功能至关重要,这有可能阐明m6A调控在男性不育症中的关键临床意义。
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来源期刊
四川大学学报(医学版)
四川大学学报(医学版) Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
0.70
自引率
0.00%
发文量
8695
期刊介绍: "Journal of Sichuan University (Medical Edition)" is a comprehensive medical academic journal sponsored by Sichuan University, a higher education institution directly under the Ministry of Education of the People's Republic of China. It was founded in 1959 and was originally named "Journal of Sichuan Medical College". In 1986, it was renamed "Journal of West China University of Medical Sciences". In 2003, it was renamed "Journal of Sichuan University (Medical Edition)" (bimonthly). "Journal of Sichuan University (Medical Edition)" is a Chinese core journal and a Chinese authoritative academic journal (RCCSE). It is included in the retrieval systems such as China Science and Technology Papers and Citation Database (CSTPCD), China Science Citation Database (CSCD) (core version), Peking University Library's "Overview of Chinese Core Journals", the U.S. "Index Medica" (IM/Medline), the U.S. "PubMed Central" (PMC), the U.S. "Biological Abstracts" (BA), the U.S. "Chemical Abstracts" (CA), the U.S. EBSCO, the Netherlands "Abstracts and Citation Database" (Scopus), the Japan Science and Technology Agency Database (JST), the Russian "Abstract Magazine", the Chinese Biomedical Literature CD-ROM Database (CBMdisc), the Chinese Biomedical Periodical Literature Database (CMCC), the China Academic Journal Network Full-text Database (CNKI), the Chinese Academic Journal (CD-ROM Edition), and the Wanfang Data-Digital Journal Group.
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