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

Abstract

Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P₄) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that <i>N⁶</i>-methyladenosine (m⁶A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P₄ signaling. Conditional deletion of methyltransferase-like 3 (<i>Mettl3</i>), encoding the m⁶A writer METTL3, in the female reproductive tract using a Cre mouse line with <i>Pgr</i> promoter (<i>Pgr-Cre</i>) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of <i>Mettl3</i> null mice failed to respond to artificial decidualization. We further found that <i>Mettl3</i> deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that <i>Pgr</i> mRNA is a direct target for METTL3-mediated m⁶A modification. A luciferase assay revealed that the m⁶A modification in the 5' untranslated region (5'-UTR) of <i>Pgr</i> 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 P₄ signaling during embryo implantation via m⁶A-mediated translation control of <i>Pgr</i> mRNA.