The Latest Research Progress of m6A Modification and Its Writers, Erasers, Readers in Infertility: A Review

Abstract

Eukaryotic messenger mRNAs contain many RNA methyl chemical modifications, in which N6-methyladenosine (m6A) plays a very important role. The modification process of RNA methylation is a dynamic reversible regulatory process that is mainly catalyzed by “Writer” m6A methyltransferase, removed by “Eraser” m6A demethylase, and recognized by the m6A binding protein, thereby, linking m6A modification with other mRNA pathways. At various stages of the life cycle, m6A modification plays an extremely important role in regulating mRNA splicing, processing, translation, as well as degradation, and is associated with gametogenesis and fertility for both sexes. Normal gametogenesis is a basic guarantee of fertility. Infertility leads to trauma, affects harmony in the family and seriously affects the quality of life. We review the roles and mechanisms of RNA m6A methylation modification in infertility and provide a potential target for infertility treatment, which can be used for drug development.

Connecting the Dots: N6‐Methyladenosine (m6A) Modification in Spermatogenesis

“…YTHDC2 is highly expressed in the testes and has been linked to spermatogenesis in recent studies. [19][20][21][22][23]48,[66][67][68][69][70][71] YTHDC2 was highly expressed in pachytene spermatocytes (Figure 1A), which was consistent with the experimental validation. [48] Several studies have found that YTHDC2 regulates meiosis via different signaling pathways.…”

“…[49] Recent studies have shown that YTHDF2 is required for the development of spermatogonia. [20][21][22][23] The inhibition of the G2 phase in GC-1 cells was caused by Ythdf2 depletion. Furthermore, YTHDF2 modulated cell-matrix adhesion mainly by regulating matrix metallopeptidase (MMPs) and extracellular matrix (ECMs) expression, and matrix metallopeptidase 13 (Mmp13) is an important target for YTHDF2 to regulate the phenotype.…”

“…Vasa-cre-mediated ablation of Mettl3 in germ cells strongly inhibits sperm differentiation, resulting in SSCs pool depletion. [16,[19][20][21][22][23]62] In undifferentiated spermatogonia, METTL3 or METTL14 inactivation causes a decrease in m 6 A levels. Translational dysregulation of methylated transcripts affects genes involved in SCCs proliferation and differentiation, such as inhibitor of DNA binding 4 (Id4), zinc finger and BTB domain containing 16 (Zbtb16/Plzf), spermatogenesis and oogenesis specific basic helix-loop-helix 2 (Sohlh2), and DNA methyltransferase 3B (Dnmt3b).…”

“…Recent studies have summarized the role of m 6 A in spermatogenesis. [19][20][21][22][23] However, the mechanism by which m 6 A catalase enzymes contribute to specific germ cell stages remains unknown. Single-cell sequencing (scRNA-seq) techniques allow us to visualize the expression profile of m 6 A catalase enzymes in different germ cells.…”

RNA m6A modifications in mammalian gametogenesis and pregnancy

“…Precise treatment of m6A-related gene targets, including but not limited to METTL3, METTL14, WTAP, KIAA1429, FTO, YTHDC1, YTHDC2, and YTHDF2, by regulating RNA m6A modifications, can potentially ensure normal gametogenesis, which has a therapeutic effect on infertility. Since miR-186, miR-4429, miR-600, and STM2457 have been shown to target METTL3 mRNA and inhibit its expression (Zeng et al 2020, Yankova et al 2021, Wu et al 2022), these three micro-RNAs and STM2457 can be used in the treatment of gametogenesis disorders (Liu et al 2021). FTO inhibitors are used in patients with FTO gene abnormalities.…”