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FTO regulates ocular angiogenesis via m6A-YTHDF2-dependent mechanism
Kun Shan1, Rong-Mei Zhou1, Jun Xiang1
1Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, China.
Abstract:
Pathological ocular angiogenesis commonly results in visual impairment or even blindness. Unveiling the mechanisms of pathological angiogenesis is critical to identify the regulators and develop effective targeted therapies. Here, we used corneal neovascularization (CNV) model to investigate the mechanism of pathological ocular angiogenesis. We show that N6-methyladenosine (m6A) mRNA demethylation mediated by fat mass- and obesity-associated protein (FTO) could regulate endothelial cell (EC) function and pathological angiogenesis during CNV. FTO levels are increased in neovascularized corneas and ECs under pathological conditions. In vitro silencing of FTO in ECs results in reduced cellular proliferation, migration, and tube formation under both basal and pathological conditions. Furthermore, FTO silencing attenuates suture-induced CNV in vivo. Mechanically, FTO silencing in ECs could increase m6A methylation levels in critical pro-angiogenic genes, such as FAK, leading to decreased RNA stability and increased RNA decay through m6A reader YTHDF2. Our study demonstrates that FTO regulates pathological ocular angiogenesis by controlling EC function in an m6A-YTHDF2-dependent manner.
Insights
Fat mass- and obesity-associated protein (FTO) regulates pathological ocular angiogenesis by affecting endothelial cell function. This involves N6-methyladenosine (m6A) mRNA demethylation, impacting gene stability and crucial for developing targeted therapies.
Area of Science:
- Ophthalmology
- Molecular Biology
- Epigenetics
Background:
- Pathological ocular angiogenesis leads to vision loss.
- Understanding its mechanisms is key for developing treatments.
- N6-methyladenosine (m6A) modification plays a role in cellular processes.
Purpose of the Study:
- Investigate the role of FTO-mediated m6A demethylation in pathological ocular angiogenesis.
- Determine FTO's impact on endothelial cell function and corneal neovascularization (CNV).
Main Methods:
- Utilized a corneal neovascularization (CNV) mouse model.
- Performed in vitro experiments involving endothelial cell (EC) FTO silencing.
- Assessed EC proliferation, migration, and tube formation.
- Analyzed m6A levels, RNA stability, and gene expression (e.g., FAK).
Main Results:
- FTO levels were elevated in neovascularized corneas and ECs.
- FTO silencing reduced EC proliferation, migration, and tube formation.
- In vivo FTO silencing attenuated CNV.
- FTO inhibition increased m6A methylation of pro-angiogenic genes (e.g., FAK), enhancing RNA decay via YTHDF2.
Conclusions:
- FTO promotes pathological ocular angiogenesis by regulating EC function.
- The mechanism involves m6A demethylation and the YTHDF2 reader.
- FTO is a potential therapeutic target for ocular angiogenesis disorders.
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