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RNF126 Promotes Endoplasmic Reticulum Stress in Fetal Growth Restriction via Ubiquitination-Mediated Degradation of the MYH9/MYH10 Complex

ABSTRACT: Fetal growth restriction (FGR) stands as a prominent cause of neonatal morbidity and mortality, yet its underlying mechanisms remain elusive. Through a multi-omics analysis of the human placentas, including quantitative proteomics and ubiquitination-modified proteomics, our team find that the E3 ligase Ring finger protein 126 (RNF126) might be a potentially pivotal protein in the development of FGR. Here, we have discovered that RNF126 can induce endoplasmic reticulum stress (ERS) in placental trophoblasts through RNA sequencing, leading to an increase in apoptosis rates. Subsequent studies have confirmed that RNF126 promotes the degradation of the MYH9/MYH10 complex via the ubiquitin-proteasome pathway, thereby contributing to ERS and inducing trophoblast dysfunction. Meanwhile, Our RNF126 placenta-specific knockout mouse model (cKO) validates these findings in vivo. These events significantly contribute to the occurrence and progression of FGR. This study provides new insights and highlights the promising potential of RNF126 as a therapeutic target for FGR treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285829 | GEO | 2025/06/20

REPOSITORIES: GEO

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Project description:Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classical epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in hypertensive patients is important for investigating novel hypertension mechanisms.Differential genomic DNA methylation in hypertensive, prehypertensive, and healthy control individuals was screened using the Illumina 450K BeadChip and verified by pyrosequencing. Plasma oviduct glycoprotein 1 (OVGP1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein–protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays. We found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilatation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, Ovgp1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that myosin heavy chain II-A (MYH9) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling. CONCLUSIONS: Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

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RNF126 Promotes Endoplasmic Reticulum Stress in Fetal Growth Restriction via Ubiquitination-Mediated Degradation of the MYH9/MYH10 Complex

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