METTL3 is essential for normal progesterone signaling during embryo implantation via m(6)A-mediated translation control of progesterone receptor

Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P(4)) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N(6)-methyladenosine (m(6)A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P(4) signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m(6)A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m(6)A modification. A luciferase assay revealed that the m(6)A modification in the 5′ untranslated region (5′-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P(4) signaling during embryo implantation via m(6)A-mediated translation control of Pgr mRNA.