METTL3 is essential for normal progesterone signaling during embryo implantation via m6A-mediated translation control of progesterone receptor

Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2214684120. doi: 10.1073/pnas.2214684120. Epub 2023 Jan 24.

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 N6-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 (Mettl3), encoding the m6A 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 m6A modification. A luciferase assay revealed that the m6A 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 P4 signaling during embryo implantation via m6A-mediated translation control of Pgr mRNA.

Keywords: METTL3; embryo implantation; m6A; progesterone receptor.

MeSH terms

  • Animals
  • Embryo Implantation / genetics
  • Female
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Knockout
  • Progesterone* / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Progesterone* / genetics
  • Receptors, Progesterone* / metabolism
  • Uterus / metabolism

Substances

  • Progesterone
  • Receptors, Progesterone
  • Methyltransferases
  • RNA, Messenger
  • METTL3 protein, human
  • Mettl3 protein, mouse