ArticleJournal of translational medicine2023
The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy.
Article in Journal of translational medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 28 citations in OpenAlex.
- Clonal Hematopoiesis of Indeterminate Potential (CHIP): A Model of Mutation-Driven Thromboinflammation.Cancers · 2026Review
- Ferroptosis in diabetic retinopathy: cellular heterogeneity, progression, and therapeutic targets.Molecular biology reports · 2026Review
- Occludin-mediated barrier dysfunction and its role in cardiovascular and cerebrovascular pathogenesis.Frontiers in cardiovascular medicine · 2026Review
- Ferroptosis in diabetic retinopathy: from pathogenic mechanisms to translational prospects.Frontiers in endocrinology · 2026Review
- SP1-activated CFL2 promotes high glucose-induced retinal pigment epithelial cell injury and involves the AMPK/mTOR pathway.Journal of diabetes investigation · 2025Article
- Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy.Nature communications · 2025Article
- Ten-Eleven Translocation Family Proteins: Structure, Biological Functions, Diseases, and Targeted Therapy.MedComm · 2025Review
- Unravelling the role of TET2 in venous thromboembolism: insights into mechanisms and therapeutic implications.Frontiers in cardiovascular medicine · 2025Review
- Hypoxia-induced P4HA1 overexpression promotes post-ischemic angiogenesis by enhancing endothelial glycolysis through downregulating FBP1.Journal of translational medicine · 2024Article
- TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy.Clinical epigenetics · 2024Article
- Traversing the epigenetic landscape: DNA methylation from retina to brain in development and disease.Frontiers in cellular neuroscience · 2024Review
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5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundIn diabetic retinopathy, increasing evidence points to a link between the pathogenesis of retinal microangiopathy and the endothelial cell-specific factor roundabout4 (ROBO4). According to earlier research, specificity protein 1 (SP1) enhances the binding to the ROBO4 promoter, increasing Robo4 expression and hastening the progression of diabetic retinopathy. To determine if this is related to aberrant epigenetic modifications of ROBO4, we examined the methylation level of the ROBO4 promoter and the corresponding regulatory mechanism during the course of diabetic retinopathy and explored the effect of this mechanism on retinal vascular leakage and neovascularization.
methodsThe methylation level of CpG sites in the ROBO4 promoter was detected in human retinal endothelial cells (HRECs) cultured under hyperglycemic conditions and retinas from streptozotocin-induced diabetic mice. The effects of hyperglycemia on DNA methyltransferase 1, Tet methylcytosine dioxygenase 2 (TET2), 5-methylcytosine, 5-hydroxymethylcytosine, and the binding of TET2 and SP1 to the ROBO4 promoter, as well as the expression of ROBO4, zonula occludens 1 (ZO-1) and occludin were examined. Short hairpin RNA was used to suppress the expression of TET2 or ROBO4 and the structural and functional changes in the retinal microvascular system were assessed.
resultsIn HRECs cultured under hyperglycemic conditions, the ROBO4 promoter methylation level decreased. Hyperglycemia-induced TET2 overexpression caused active demethylation of ROBO4 by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, which enhanced the binding of SP1 to ROBO4, increased the expression of ROBO4, and decreased the expression of ZO-1 and occludin, leading to the abnormalities in monolayer permeability, migratory ability and angiogenesis of HRECs. The above pathway was also demonstrated in the retinas of diabetic mice, which caused leakage from retinal capillaries and neovascularization. Inhibition of TET2 or ROBO4 expression significantly ameliorated the dysfunction of HRECs and retinal vascular abnormalities.
conclusionsIn diabetes, TET2 can regulate the expression of ROBO4 and its downstream proteins by mediating active demethylation of the ROBO4 promoter, which accelerates the development of retinal vasculopathy. These findings suggest that TET2-induced ROBO4 hypomethylation is a potential therapeutic target, and anti- TET2/ROBO4 therapy is anticipated to emerge as a novel strategy for early intervention and delayed progression of diabetic retinopathy.
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