image: Successful pregnancy requires coordinated physiological processes, with m⁶A participating in critical stages: i) Folliculogenesis: m⁶A dynamically regulates oocyte-granulosa cell crosstalk during follicular maturation from primordial follicles to metaphase II (MII) oocytes, mediated by key regulators including METTL3, METTL14, KIAA1429, FTO, YTHDC1, YTHDC2, and IGF2BP1. ii) Embryogenesis: Following fertilization, m⁶A governs epigenetic modulation of zygotic development from the 2-cell stage through blastocyst formation. iii) Embryo implantation: Endometrial receptivity, a pivotal determinant of implantation success, is enhanced by m⁶A-mediated homeostatic control of hormonal metabolic signaling, involving METTL3, METTL14, METTL16, WTAP, and IGF2BP2. iv) Immune microenvironment: Embryo-derived immunomodulatory factors recruit immune cells to coordinate developmental processes. m⁶A regulators such as METTL3, METTL14, IGF2BP2, ALKBH5, and YTHDF2 modulate T cell/NK cell activities during immune adaptation. METTL3/14/16, methyltransferase 3/14/16; ALKBH5, ALKB homologue 5; FTO, fat mass and obesity-associated protein; YTHDC1/2, YTH domain containing 1/2; WTAP, Wilms tumor 1-associated protein; KIAA1429, also called VIRMA, vir-Like m⁶A methyltransferase associated, VIRILIZER; IGF2BP1/2, insulin-like growth factor-2 mRNA-binding protein 1/2; YTHDF2, YTH domain family 2; NK, natural killer.
Credit: Jie Ding, Yalun He, Yangshuo Li, Shuai Sun, Wen Cheng, Jiami Huang, Chaoqin Yu
N⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification in eukaryotes, regulating RNA splicing, translation, stability, and degradation. This reversible modification is dynamically controlled by three groups of proteins—“writers,” “erasers,” and “readers.” The writers (e.g., METTL3, METTL14, and WTAP) install methyl groups onto RNA, the erasers (such as FTO and ALKBH5) remove them to maintain epigenetic balance, and the readers (YTH and IGF2BP family proteins) interpret these methylation marks to fine-tune gene expression. Together, they form a central regulatory network essential for normal reproductive physiology and fertility.
A recent review published in Genes & Diseases by researchers at The First Affiliated Hospital of Naval Medical University, Fudan University, and Shanghai University of Traditional Chinese Medicine provides a comprehensive overview of how m⁶A RNA methylation governs female reproductive physiology and contributes to infertility-associated disorders.
The review systematically analyzes the influence of m⁶A across multiple dimensions of female reproduction, including oocyte maturation, granulosa cell function, endometrial receptivity, immune modulation, and systemic metabolic balance. The authors describe m⁶A as a dynamic molecular switch, coordinated by writers, erasers, and readers to fine-tune stage-specific gene expression throughout the reproductive cycle.
Notably, the review highlights that dysregulation of m⁶A-related mechanisms underlies key pathologies including endometriosis, polycystic ovary syndrome (PCOS), and recurrent miscarriage, linking aberrant RNA methylation to disrupted fertility networks. Moreover, m⁶A modifications bridge reproductive and metabolic processes, affecting energy regulation, inflammation, and stress responses, all of which are critical for successful conception and pregnancy maintenance.
The authors emphasize the clinical potential of m⁶A-modifying enzymes as diagnostic biomarkers and therapeutic targets. Given its reversible nature, m⁶A methylation represents a promising avenue for developing epigenetic interventions aimed at restoring reproductive homeostasis and treating infertility-related conditions.
Despite these advances, challenges remain, including limited clinical validation, unresolved mechanistic details of specific m⁶A sites, and an insufficient exploration of m⁶A–immune interactions in reproductive contexts. The review calls for multi-omics and organoid-based approaches to map the spatiotemporal dynamics of m⁶A regulation in human reproductive tissues.
Ultimately, the authors advocate for translational research to harness m⁶A pathways for clinical benefit, alongside deeper mechanistic studies investigating cell-type-specific roles and interactions with epigenetic and metabolic networks that shape female fertility.
Reference
Title of Original Paper: The role of m⁶A methylation in female reproductive physiology and pathology
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101755
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