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METTL3 通过 mA 介导的孕激素受体翻译控制对胚胎植入过程中孕激素信号的正常传递至关重要。

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

机构信息

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.

Department of Obstetrics and Gynecology, Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510642, China.

出版信息

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

DOI:10.1073/pnas.2214684120
PMID:36693099
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9945998/
Abstract

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

摘要

胚胎着床是人类生殖过程中的一个关键步骤，它受到雌激素和孕激素（P）的严格控制，分别通过雌激素受体 alpha 和孕激素受体（PGR）来实现。在这里，我们报告说，在真核生物中最丰富的 mRNA 修饰——N6-甲基腺苷（m6A），通过维持 P 信号通路，在胚胎着床中发挥着重要作用。利用含有启动子（）的 Cre 小鼠系，在雌性生殖道中条件性敲除编码 m6A 写入酶 METTL3 的甲基转移酶样 3 ()，导致着床前胚胎丢失和子宫容受性缺陷，从而导致完全着床失败。此外，缺失 会导致子宫对人工蜕膜化反应不良。我们进一步发现，缺失伴随着 PGR 蛋白表达的显著减少。从机制上讲，我们发现 mRNA 是 METTL3 介导的 m6A 修饰的直接靶标。荧光素酶报告基因实验显示，METTL3 介导的 mRNA 5'非翻译区（5'-UTR）中的 m6A 修饰以 YTHDF1 依赖的方式增强 PGR 蛋白的翻译效率。最后，我们证明了 METTL3 在体外人子宫内膜基质细胞蜕膜化过程中是必需的，并且 METTL3-PGR 轴在小鼠和人类之间是保守的。总之，这项研究提供了证据，表明 METTL3 通过 m6A 介导的 mRNA 翻译控制在胚胎着床过程中对正常的 P 信号至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/db39b00e85bf/pnas.2214684120fig09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/728308d11cf0/pnas.2214684120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/90a5b2984d2e/pnas.2214684120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/23f301abf877/pnas.2214684120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/f4f272ccaf23/pnas.2214684120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/6e78f4f44dd2/pnas.2214684120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/1640d27c0dd2/pnas.2214684120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/2378a52ccd6b/pnas.2214684120fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/d8f645be3c5d/pnas.2214684120fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/db39b00e85bf/pnas.2214684120fig09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/728308d11cf0/pnas.2214684120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/90a5b2984d2e/pnas.2214684120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/23f301abf877/pnas.2214684120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/f4f272ccaf23/pnas.2214684120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/6e78f4f44dd2/pnas.2214684120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/1640d27c0dd2/pnas.2214684120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/2378a52ccd6b/pnas.2214684120fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/d8f645be3c5d/pnas.2214684120fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8eaa/9945998/db39b00e85bf/pnas.2214684120fig09.jpg

相似文献

[1]
METTL3 is essential for normal progesterone signaling during embryo implantation via mA-mediated translation control of progesterone receptor.

Proc Natl Acad Sci U S A. 2023-1-31

[2]
METTL3-dependent mA methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling.

Cell Death Dis. 2023-6-3

[3]
Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation.

Endocrinology. 2020-12-1

[4]
METTL3-regulated m6A modification impairs the decidualization of endometrial stromal cells by regulating YTHDF2-mediated degradation of FOXO1 mRNA in endometriosis-related infertility.

Reprod Biol Endocrinol. 2023-10-27

[5]
CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis.

Nat Commun. 2023-6-3

[6]
Increased METTL3-mediated mA methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure.

Reprod Biol Endocrinol. 2021-12-14

[7]
Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility.

Proc Natl Acad Sci U S A. 2016-2-23

[8]
Aberrant activation of estrogen receptor-α signaling in Mettl14-deficient uteri impairs embryo implantation.

FASEB J. 2023-8

[9]
Estrogen induces EGR1 to fine-tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation.

FASEB J. 2018-1-3

[10]
FOXO1 regulates uterine epithelial integrity and progesterone receptor expression critical for embryo implantation.

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引用本文的文献

[1]
m6A Methylation Modification: Perspectives on the Early Reproduction of Females.

Biomolecules. 2025-7-31

[2]
Advances in research on RNA methylation and cancer radiotherapy resistance.

Front Oncol. 2025-7-31

[3]
YTHDC1 Promoted Cell Proliferation and Decidualization by Maintaining Nuclear C/EBPβ Stability in Decidual Stromal Cells.

Reprod Sci. 2025-6-4

[4]
Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition.

Matern Fetal Med. 2024-1-15

[5]
Structural proteomics defines a sequential priming mechanism for the progesterone receptor.

Nat Commun. 2025-5-12

[6]
Epigenetics of maternal-fetal interface immune microenvironment and placental related pregnancy complications.

Front Immunol. 2025-4-3

[7]
Understanding epigenetic regulation in the endometrium - lessons from mouse models with implantation defects.

Epigenomics. 2025-6

[8]
Mettl3/Eed/Ythdc1 regulatory axis controls endometrial receptivity and function.

Commun Biol. 2025-2-11

[9]
Epigenetic regulation in female reproduction: the impact of m6A on maternal-fetal health.

Cell Death Discov. 2025-2-4

[10]
Structural proteomics defines a sequential priming mechanism for the progesterone receptor.

Res Sq. 2024-11-14

本文引用的文献

[1]
Characterization of placental and decidual cell development in early pregnancy loss by single-cell RNA sequencing.

Cell Biosci. 2022-10-8

[2]
Single-cell transcriptome profiling of the human endometrium of patients with recurrent implantation failure.

Theranostics. 2022

[3]
mA mRNA methylation regulates the ERK/NF-κB/AKT signaling pathway through the PAPPA/IGFBP4 axis to promote proliferation and tumor formation in endometrial cancer.

Cell Biol Toxicol. 2023-8

[4]
P38α MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation.

Proc Natl Acad Sci U S A. 2022-8-9

[5]
Hidden codes in mRNA: Control of gene expression by mA.

Mol Cell. 2022-6-16

[6]
Extensive protein dosage compensation in aneuploid human cancers.

Genome Res. 2022-7

[7]
YTHDF3 modulates hematopoietic stem cells by recognizing RNA mA modification on .

Haematologica. 2022-10-1

[8]
N-methyladenosine modification regulates imatinib resistance of gastrointestinal stromal tumor by enhancing the expression of multidrug transporter MRP1.

Cancer Lett. 2022-4-1

[9]
Increased METTL3-mediated mA methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure.

Reprod Biol Endocrinol. 2021-12-14

[10]
Deciphering mouse uterine receptivity for embryo implantation at single-cell resolution.

Cell Prolif. 2021-11

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