Exploration of the Potential Roles of M6A Regulators in the Uterus in Pregnancy and Infertility

Infertility is a prevalent female reproductive disease worldwide. Currently, there are many unknown etiologies of infertility. N6-methyladenosine (m6A) is the most prevalent modification of eukaryotic mRNA. This study intended to investigate the implications of m6A regulators in the uterus for pregnancy and infertility. Pregnant ICR mice on days (D) 0, 4, 6, 10, and 15 were used to monitor m6A methylation in the uterus by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then m6A methylation regulators were detected by real-time quantitative PCR (qPCR), western blot and immunohistochemistry (IHC). We found that m6A levels increased and that m6A regulators were expressed differently in the uterus during pregnancy. Then, we acquired expression data from endometrial tissue from women with infertility and recurrent pregnancy loss from the Gene Expression Omnibus (GEO) database. The expression of m6A regulators in infertility was significantly dysregulated according to the data mining technique. Specifically, the mRNA levels of METTL16 (p = 0.0147) and WTAP (p = 0.028) were lower and those of ALKBH5 (p = 0.0432) and IGF2BP2 (p = 0.0016) were higher in the endometrium of infertile patients. Meanwhile, many immunity-related pathways are abnormal in infertility, such as cytokine-cytokine receptor interactions, natural killer cell-mediated cytotoxicity and leukocyte transendothelial migration. In conclusion, we found that the m6A levels in the uterus increased as pregnancy progressed, and these regulators were dysregulated in the endometrium of infertility patients. These results suggest that m6A methylation may be very important in the establishment of implantation and maintenance of pregnancy and may become a new direction for research on infertility.