TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy

被引:4
作者
Cai, Chunyang [1 ,3 ]
Gu, Chufeng [1 ,3 ]
He, Shuai [1 ,3 ]
Meng, Chunren [1 ,3 ]
Lai, Dongwei [1 ,3 ]
Zhang, Jingfa [1 ,3 ]
Qiu, Qinghua [2 ,4 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Ophthalmol, 100 Haining Rd, Shanghai 200080, Peoples R China
[2] Shanghai Jiao Tong Univ, Tong Ren Hosp, Dept Ophthalmol, Sch Med, 1111 Xianxia Rd, Shanghai 200050, Peoples R China
[3] Shanghai Engn Ctr Precise Diag & Treatment Eye Dis, Shanghai Engn Ctr Visual Sci & Photomed, Shanghai Key Lab Ocular Fundus Dis, Natl Clin Res Ctr Eye Dis, Shanghai, Peoples R China
[4] Shigatse Peoples Hosp, Dept Ophthalmol, Shigatse, Xizang, Peoples R China
基金
中国国家自然科学基金;
关键词
Proliferative diabetic retinopathy (PDR); Neovascularization; TET2; ECM1; DNA methylation; Epigenetics; DNA METHYLATION; EXPRESSION; EPSILON;
D O I
10.1186/s13148-023-01619-1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundStudies have shown that tet methylcytosine dioxygenase 2 (TET2) is highly expressed in diabetic retinopathy (DR), which reduces the DNA methylation of downstream gene promoters and activates the transcription. Abnormally expressed TET2 and downstream genes in a high-glucose environment are associated with retinal capillary leakage and neovascularization. Here, we investigated the downstream genes of TET2 and its potential association with neovascularization in proliferative diabetic retinopathy (PDR).MethodsGSE60436, GSE57362, and GSE158333 datasets were analyzed to identify TET2-related hypomethylated and upregulated genes in PDR. Gene expression and promoter methylation of these genes under high glucose treatment were verified. Moreover, TET2 knockdown was used to assess its impact on tube formation and migration in human retinal microvascular endothelial cells (HRMECs), as well as its influence on downstream genes.ResultsOur analysis identified three key genes (PARVB, PTPRE, ECM1) that were closely associated with TET2 regulation. High glucose-treated HRMECs exhibited increased expression of TET2 and ECM1 while decreasing the promoter methylation level of ECM1. Subsequently, TET2 knockdown led to decreased migration ability and tube formation function of HRMECs. We further found a decreased expression of PARVB, PTPRE, and ECM1, accompanied by an increase in the promoter methylation of ECM1.ConclusionsOur findings indicate the involvement of dysregulated TET2 expression in neovascularization by regulating the promoter methylation and transcription of downstream genes (notably ECM1), eventually leading to PDR. The TET2-induced hypomethylation of downstream gene promoters represents a potential therapeutic target and offers a novel perspective on the mechanism underlying neovascularization in PDR.
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页数:14
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