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

Zheng, Zhan Hong ; Zhang, Guo Le ; Jiang, Run Fu ; Hong, Yu Qi ; Zhang, Qing Yan ; He, Jia Peng ; Liu, Xin Ru ; Yang, Zhen Shan LU orcid ; Yang, Liu and Jiang, Xing , et al. (2023) In Proceedings of the National Academy of Sciences of the United States of America 120(5).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
embryo implantation, mA, METTL3, progesterone receptor
in
Proceedings of the National Academy of Sciences of the United States of America
volume
120
issue
5
article number
e2214684120
publisher
National Academy of Sciences
external identifiers
  • pmid:36693099
  • scopus:85147047956
ISSN
0027-8424
DOI
10.1073/pnas.2214684120
language
English
LU publication?
no
additional info
Funding Information: ACKNOWLEDGMENTS. This research was funded by National Natural Science Foundation of China (32070845 and 31771665), Guangdong Natural Science Funds for Distinguished Young Scholars (2021B1515020079), Innovation Team Project of Guangdong University (2019KCXTD001), Guangdong Special Support Program (2019BT02Y276) and National Key R&D Program of China (2018YFA0801404). Publisher Copyright: Copyright © 2023 the Author(s). Published by PNAS.
id
de83e0da-a09d-4ede-ba2c-f31386259a53
date added to LUP
2024-02-28 15:00:43
date last changed
2024-04-27 18:40:37
@article{de83e0da-a09d-4ede-ba2c-f31386259a53,
  abstract     = {{<p>Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P<sub>4</sub>) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N<sup>6</sup>-methyladenosine (m<sup>6</sup>A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P<sub>4</sub> signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m<sup>6</sup>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<sup>6</sup>A modification. A luciferase assay revealed that the m<sup>6</sup>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<sub>4</sub> signaling during embryo implantation via m<sup>6</sup>A-mediated translation control of Pgr mRNA.</p>}},
  author       = {{Zheng, Zhan Hong and Zhang, Guo Le and Jiang, Run Fu and Hong, Yu Qi and Zhang, Qing Yan and He, Jia Peng and Liu, Xin Ru and Yang, Zhen Shan and Yang, Liu and Jiang, Xing and Qu, Li Jian and Ding, Chen Hui and Xu, Yan Wen and Yang, Shi Hua and Liu, Ji Long}},
  issn         = {{0027-8424}},
  keywords     = {{embryo implantation; mA; METTL3; progesterone receptor}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{5}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{METTL3 is essential for normal progesterone signaling during embryo implantation via m<sup>6</sup>A-mediated translation control of progesterone receptor}},
  url          = {{http://dx.doi.org/10.1073/pnas.2214684120}},
  doi          = {{10.1073/pnas.2214684120}},
  volume       = {{120}},
  year         = {{2023}},
}