Placenta · 2026
METTL3-regulated m6A modification modulates autophagy of placental mesenchymal stem/stromal cell by YTHDF3-mediated degradation of LncRNA GAS5 in preeclampsia.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhang Yang, Wu Di, Zou Li, Cheng Xiangwei, Liu Xiaoxia
Аннотация
BACKGROUND: Preeclampsia (PE) causes maternal and perinatal morbidity through defective placental vascularization. Autophagy enhances placental mesenchymal stem/stromal cells (PMSC) proangiogenic properties while autophagy is reduced in PE. Long non-coding RNA GAS5, elevated in PE placenta, suppresses endothelial angiogenesis. N6-methyladenosine (m6A) modification through METTL3 regulates RNA stability and autophagy. However, regulatory mechanisms governing PMSC autophagy in PE remain unclear.
METHOD: Placenta specimens and PMSC from the normal and PE were compared. Molecular analyses included qRT-PCR, Western blotting, and m6A level evaluation. Transfections used siRNA knockdown and plasmid overexpression with rescue experiments. Autophagy was evaluated through LC3-II/LC3-I ratios and p62. Cellular functional assessments comprised CKK8 assays, ELISA for VEGF secretion, and tube formation for angiogenesis. MeRIP-PCR, RNA pull-down assay and RNA immunoprecipitation PCR identified m6A-modified transcripts.
RESULT: PE placenta and PMSC demonstrated significantly reduced METTL3 expression and global m6A modification levels, accompanied by elevated GAS5 expression. METTL3 overexpression enhanced PMSC autophagy, cell proliferation, VEGF secretion, and angiogenic capacity, while GAS5 exhibited opposing effects. GAS5 knockdown rescued PMSC autophagy and dysfunction caused by METTL3 deficiency. Mechanistically, METTL3 catalyzed m6A modification of GAS5 transcripts, facilitating YTHDF3-mediated recognition and degradation. YTHDF3 depletion reversed METTL3-induced autophagy improvements, confirming the regulatory cascade.
CONCLUSION: Our findings establish a novel epigenetic regulatory network wherein METTL3/YTHDF3-mediated GAS5 degradation controls PMSC autophagy in PE. This pathway represents a potential therapeutic target for ameliorating placental vascularization defects in PE.
METHOD: Placenta specimens and PMSC from the normal and PE were compared. Molecular analyses included qRT-PCR, Western blotting, and m6A level evaluation. Transfections used siRNA knockdown and plasmid overexpression with rescue experiments. Autophagy was evaluated through LC3-II/LC3-I ratios and p62. Cellular functional assessments comprised CKK8 assays, ELISA for VEGF secretion, and tube formation for angiogenesis. MeRIP-PCR, RNA pull-down assay and RNA immunoprecipitation PCR identified m6A-modified transcripts.
RESULT: PE placenta and PMSC demonstrated significantly reduced METTL3 expression and global m6A modification levels, accompanied by elevated GAS5 expression. METTL3 overexpression enhanced PMSC autophagy, cell proliferation, VEGF secretion, and angiogenic capacity, while GAS5 exhibited opposing effects. GAS5 knockdown rescued PMSC autophagy and dysfunction caused by METTL3 deficiency. Mechanistically, METTL3 catalyzed m6A modification of GAS5 transcripts, facilitating YTHDF3-mediated recognition and degradation. YTHDF3 depletion reversed METTL3-induced autophagy improvements, confirming the regulatory cascade.
CONCLUSION: Our findings establish a novel epigenetic regulatory network wherein METTL3/YTHDF3-mediated GAS5 degradation controls PMSC autophagy in PE. This pathway represents a potential therapeutic target for ameliorating placental vascularization defects in PE.