Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors

Liu, Shuai; Lao, Yongfeng; Wang, Yanan; Li, Rongxin; Fang, Xuefeng; Wang, Yunchang; Gao, Xiaolong; Dong, Zhong

doi:10.3389/fcell.2021.676364

Cited by 11 publications

(9 citation statements)

References 148 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The m 6 A RNA modification has been demonstrated by compelling evidence to be essential for mouse spermatogenesis. Studies on knockout models of m 6 A-associated factors, including writers, readers and erasers, have revealed that m 6 A participates in the precise regulation of spermatogonial differentiation, meiosis and spermiogenesis ( 55 , 56 ). Germ cell-specific ablation of the m 6 A methyltransferase complex core catalytic subunit protein METTL3 or scaffolding protein METTL14 with Vasa-Cre causes exhaustion of the spermatogonial stem cell pool due to excessive spermatogonial proliferation ( 37 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

NAT10-mediated N4-acetylcytidine modification is required for meiosis entry and progression in male germ cells

Chen

Wang

Liu

et al. 2022

Nucleic Acids Research

View full text Add to dashboard Cite

Post-transcriptional RNA modifications critically regulate various biological processes. N4-acetylcytidine (ac4C) is an epi-transcriptome, which is highly conserved in all species. However, the in vivo physiological functions and regulatory mechanisms of ac4C remain poorly understood, particularly in mammals. In this study, we demonstrate that the only known ac4C writer, N-acetyltransferase 10 (NAT10), plays an essential role in male reproduction. We identified the occurrence of ac4C in the mRNAs of mouse tissues and showed that ac4C undergoes dynamic changes during spermatogenesis. Germ cell-specific ablation of Nat10 severely inhibits meiotic entry and leads to defects in homologous chromosome synapsis, meiotic recombination and repair of DNA double-strand breaks during meiosis. Transcriptomic profiling revealed dysregulation of functional genes in meiotic prophase I after Nat10 deletion. These findings highlight the crucial physiological functions of ac4C modifications in male spermatogenesis and expand our understanding of its role in the regulation of specific physiological processes in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

NAT10-mediated N4-acetylcytidine modification is required for meiosis entry and progression in male germ cells

Chen

Wang

Liu

et al. 2022

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Our previous study reported that HFD resulted in increased m6A methylation levels and METTL3 expression in the myocardium of mice, while decreasing FTO expression and inducing myocardial apoptosis [ 20 ]. In addition, m6A methylation and its regulatory factors are abnormally expressed in testicular diseases, leading to testicular oxidative damage, apoptosis and reproductive dysfunction [ 13 , 15 ]. It was reported that m6A methylation levels and the expression of METTL3 and METTL14 were up-regulated in semen samples of patients with asthenozoospermia [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…m6A RNA modification is regulated by m6A-related genes, including m6A methyltransferases (methyltransferase-like 3 (METTL3), METTL14 and WT1-associated protein (WTAP), termed as “writers”), RNA demethylases (alpha-ketoglutarate-dependent dioxygenase (FTO) and AlkB homolog 5 (ALKBH5), termed as “erasers”) and RNA binding proteins (YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), YTHDF2, YTHDF3, YTH domain containing 1 (YTHDC1) and YTHDC2, termed as “readers”) [ 10 , 11 ]. Recent studies have reported that m6A RNA modification can regulate mammalian spermatogenesis and reproductive function [ 12 , 13 ]. In addition, it has been reported that m6A modification is related to obesity, oxidative stress and apoptosis [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Moderate-Intensity Continuous Training and High-Intensity Interval Training on Testicular Oxidative Stress, Apoptosis and m6A Methylation in Obese Male Mice

Qin

Bin-bin

et al. 2022

Antioxidants

View full text Add to dashboard Cite

Exercise is an effective way to improve reproductive function in obese males. Oxidative stress and apoptosis are important pathological factors of obesity-related male infertility. Accumulating studies have demonstrated that N6-methyladenosine (m6A) methylation is associated with obesity and testicular reproductive function. Our study aimed to investigate and compare the effect of 8 weeks of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on testicular oxidative stress, apoptosis and m6A methylation in obese male mice. Male C57BL/6 mice were randomly allocated into the four groups: normal diet (ND) group, high-fat diet (HFD) group, high-fat diet with moderate-intensity continuous training (HFD-MICT) group and high-fat diet with high-intensity interval training (HFD-HIIT) group. Mice in the HFD-MICT and HFD-HIIT groups were subjected to 8 weeks of MICT or HIIT treadmill protocols after 12 weeks of HFD feeding. We found that MICT and HIIT increased the protein expression of Nrf2, HO-1 and NQO-1 in the testes of obese mice, and HIIT increased it more than MICT. The Bax/Bcl-2 ratio, Cleaved Caspase-3 protein expression and TUNEL-positive cells were consistently up-regulated in the testes of obese mice, but MICT and HIIT restrained these HFD-induced effects. In addition, HFDs increased m6A levels and the gene expression of METTL3, YTHDF2 and FTO in the testes, but these effects were reversed by MICT and HIIT. However, HIIT was more effective than MICT in reducing m6A methylation in the testes of obese mice. These results demonstrate that both MICT and HIIT protected against HFD-induced oxidative stress, apoptosis and m6A methylation in testicular tissues; as a result, testicular morphological and functional impairment improved. In particular, HIIT was more beneficial than MICT in increasing the mRNA expression of steroidogenic enzymes and testicular antioxidant capacity and decreasing m6A methylation in the testes of HFD-fed mice.

show abstract

“…Among hundreds of types of RNA modifications identified [ 958 ], m 6 A is possibly the most prevalent internal, dynamic, reversible chemical modification identified to date, and plays critical roles in the growth, differentiation, and metabolism of cells [ 952 , 959 ]. An evolutionarily conserved RNA modification, m 6 A RNA methylation is involved in most aspects of RNA processing that may affect the regulation of cellular processes [ 960 ] such as immune modulation [ 961 , 962 , 963 ], fat metabolism [ 964 ], circadian rhythm [ 965 ], fertility [ 966 , 967 , 968 , 969 ], and brain plasticity and development [ 970 ].…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

View full text Add to dashboard Cite

Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

show abstract

Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors

Cited by 11 publications

References 148 publications

NAT10-mediated N4-acetylcytidine modification is required for meiosis entry and progression in male germ cells

NAT10-mediated N4-acetylcytidine modification is required for meiosis entry and progression in male germ cells

Effects of Moderate-Intensity Continuous Training and High-Intensity Interval Training on Testicular Oxidative Stress, Apoptosis and m6A Methylation in Obese Male Mice

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Contact Info

Product

Resources

About