METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling

Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m 6 A modification in infertility remains unknown. Here we report that METTL3-dependent m 6 A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation of METTL3 expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion of Mettl3 in female reproductive tract by using a Pgr -Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m 6 A-seq analysis of the uterus identifies the 3’UTR of several estrogen-responsive genes with METTL3-dependent m 6 A modification, like Elf3 and Celsr2 , whose mRNAs become more stable upon Mettl3 depletion. However, the decreased expression levels of PR and its target genes, including Myc , in the endometrium of Mettl3 cKO mice indicate a deficiency in progesterone responsiveness. In vitro, Myc overexpression could partially compensate for uterine decidualization failure caused by Mettl3 deficiency. Collectively, this study reveals the role of METTL3-dependent m 6 A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.