The Role of m6A on Female Reproduction and Fertility: From Gonad Development to Ovarian Aging

Abstract

The growth and maturation of oocyte is accompanied by the accumulation of abundant RNAs and posttranscriptional regulation. N6-methyladenosine (m6A) is the most prevalent epigenetic modification in mRNA, and precisely regulates the RNA metabolism as well as gene expression in diverse physiological processes. Recent studies showed that m6A modification and regulators were essential for the process of ovarian development and its aberrant manifestation could result in ovarian aging. Moreover, the specific deficiency of m6A regulators caused oocyte maturation disorder and female infertility with defective meiotic initiation, subsequently the oocyte failed to undergo germinal vesicle breakdown and consequently lost the ability to resume meiosis by disrupting spindle organization as well as chromosome alignment. Accumulating evidence showed that dysregulated m6A modification contributed to ovarian diseases including polycystic ovarian syndrome (PCOS), primary ovarian insufficiency (POI), ovarian aging and other ovarian function disorders. However, the complex and subtle mechanism of m6A modification involved in female reproduction and fertility is still unknown. In this review, we have summarized the current findings of the RNA m6A modification and its regulators in ovarian life cycle and female ovarian diseases. And we also discussed the role and potential clinical application of the RNA m6A modification in promoting oocyte maturation and delaying the reproduction aging.

N6-methyladenosine regulator-mediated methylation modification patterns and immune infiltration characterization in Polycystic Ovary Syndrome (PCOS)

“…PCOS is a multifactorial disease caused by genetic, endogenous, endocrine regulation, metabolic disorders, and environmental factors, and the treatment strategies for PCOS involve a combination of lifestyle optimization, medical interventions, which include metformin, hormonal contraceptives, antiandrogens, and so on, and if needed, infertility management [ 1 , 18 , 23 ]. But the diagnosis and following management are often complex and unsatisfactory, highlighting the need for further investigation of the pathogenesis of PCOS.…”

“…But the diagnosis and following management are often complex and unsatisfactory, highlighting the need for further investigation of the pathogenesis of PCOS. Existing researches have shown that m6A regulators play a role in the biological process of PCOS [ 18 , 24 ]. As most studies focus on a single m6A regulator, the overall roles of multiple m6A regulators in PCOS are not comprehensively recognized.…”

“…Previous studies have investigated and revealed the significant role of m6A RNA methylation regulators in the occurrence and progression of PCOS [ 18 ]. However, these researches concentrated predominantly on several of the 26 m6A regulators.…”

RNA N6-methyladenosine modification in female reproductive biology and pathophysiology

“…The maintenance of normal pregnancy depends on the establishment of endometrial receptivity, normal embryogenesis, and the formation of an immune microenvironment at the maternal-foetal interface. Several studies have shown that m 6 A modification is related to the regulation of physiological functions of the female reproductive system [10]. For example, by controlling the translation of Pgr mRNA through m 6 A modification, METTL3 is crucial for efficient P4 signaling during embryogenesis.…”

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N 6-methyladenosine methylation

“…Previous studies have highlighted the indispensable functions of m 6 A readers and writers in oogenesis 9 . For example, oocyte-specific loss of the m 6 A reader Ythdf2 contributes to incompetence in metaphase II (MII) oocytes leading to failure to support early zygotic development 10 .…”