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

• DOI: 10.1073/pnas.2214684120
• Publication Date: 2023-01-24T18:36:38Z
• Authors: Zhan-Hong Zheng; Guo-Le Zhang; Run-Fu Jiang; Yu-Qi Hong; Qing-Yan Zhang; Jia-Peng He; Xin-Ru Liu; Zhen-Shan Yang; Liu Yang; Xing Jiang; Li-Jian Qu; Chen-Hui Ding; Yan-Wen Xu; Shi-Hua Yang; Ji-Long Liu
• Keywords: Decidualization; Progesterone receptor

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