Placenta · 2026
METTL3-mediated N6-methyladenosine modification of LEPR is critical for fetal growth restriction.
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Li Dianjie, Jiang Jiayi, Zhong Yixiang, Luo Manling, Chen Jianhong, Li Jing, Chen Xiangli, Li Meng, Zhong Mei, Zhang Yi
Аннотация
INTRODUCTION: Fetal growth restriction (FGR) is one of the most common perinatal complications. The specific molecular mechanism remains undefined. N6-methyladenosine (m6A), the most common RNA modification in eukaryotes, is known to be associated with a variety of diseases. However, the relationships among METTL3, m6A and FGR have not been clearly reported.
METHODS: The expression of METTL3, downstream target-leptin receptor (LEPR) and m6A modification level were compared between placentas of FGR and those of normal pregnancies. C57BL/6 pregnant mice were intraperitoneally injected with the METTL3-specific inhibitor STM2457 to analyze the effects of METTL3-associated m6A methylation. Changes downstream of METTL3 were determined by RNA sequencing. The regulatory relationships among METTL3, m6A, and LEPR were explored by cell migration assay, invasion assay, CCK8 assay, Western blotting and MeRIP‒qPCR.
RESULTS: METTL3, LEPR and m6A modification were significantly decreased in the placenta of patients with FGR. After STM2457 treatment, adverse pregnancy outcomes and the FGR phenotype of fetal mice were observed. RNA-seq revealed that the downstream target of METTL3 was LEPR. The expression of LEPR was positively correlated with that of METTL3 via in vitro cellular mechanism experiments. The m6A modification level of LEPR was decreased when METTL3 was knocked down and increased when METTL3 was overexpressed. Furthermore, METTL3 and LEPR can separately or collectively promote the proliferation, migration and invasion of trophoblasts likely through m6A modification.
DISCUSSION: Our study revealed that METTL3 regulated trophoblastic function likely through an m6A-LEPR-dependent mechanism in HTR8/SVneo cells and identified a potential biomarker panel for treatment prediction in FGR.
METHODS: The expression of METTL3, downstream target-leptin receptor (LEPR) and m6A modification level were compared between placentas of FGR and those of normal pregnancies. C57BL/6 pregnant mice were intraperitoneally injected with the METTL3-specific inhibitor STM2457 to analyze the effects of METTL3-associated m6A methylation. Changes downstream of METTL3 were determined by RNA sequencing. The regulatory relationships among METTL3, m6A, and LEPR were explored by cell migration assay, invasion assay, CCK8 assay, Western blotting and MeRIP‒qPCR.
RESULTS: METTL3, LEPR and m6A modification were significantly decreased in the placenta of patients with FGR. After STM2457 treatment, adverse pregnancy outcomes and the FGR phenotype of fetal mice were observed. RNA-seq revealed that the downstream target of METTL3 was LEPR. The expression of LEPR was positively correlated with that of METTL3 via in vitro cellular mechanism experiments. The m6A modification level of LEPR was decreased when METTL3 was knocked down and increased when METTL3 was overexpressed. Furthermore, METTL3 and LEPR can separately or collectively promote the proliferation, migration and invasion of trophoblasts likely through m6A modification.
DISCUSSION: Our study revealed that METTL3 regulated trophoblastic function likely through an m6A-LEPR-dependent mechanism in HTR8/SVneo cells and identified a potential biomarker panel for treatment prediction in FGR.