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METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
Xiujuan Chen1, Qipeng Ling1, Jie Xu2
1Ophthalmology Department, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China.
Abstract:
We aimed to explore the regulatory effects of methyltransferase-like 3 (METTL3) on diabetic retinopathy (DR) by regulating the m6A modification of SOX2 mRNA and elucidating the underlying molecular mechanism. The DR model was established by stimulating human retinal endothelial cells (HRECs) with high glucose (HG). METTL3, insulin-like growth factor 2 binding protein 2 (IGF2BP2), and SOX2 levels in the sera of patients with DR and HRECs were determined using qRT-PCR and western blotting. Moreover, the interactions between SOX2 and METTL3 or IGF2BP2 were confirmed using RNA-binding protein immunoprecipitation (RIP) experiments. Furthermore, HRECs proliferation and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The protein level of cleaved-caspase3 and caspase3 in HRECs were evaluated using western blotting. The results indicated that the expression of METTL3, IGF2BP2, and SOX2 was notably decreased in the serum of patients with DR, as well as in HRECs under HGs. RIP further verified the relationship between METTL3 and SOX2 mRNA expression. HG treatment inhibited HREC viability, increased apoptosis, and enhanced cleaved-caspase3 expression and cleaved-caspase3/caspase3 ratio. Upregulation of METTL3 significantly restored the effects of HG, whereas SOX2 knockdown partially reversed the regulatory effects of METTL3 on HRECs. In summary, METTL3 blocks the progression of DR by regulating m6A modification on SOX2 mRNA.
Insights
Methyltransferase-like 3 (METTL3) regulates diabetic retinopathy (DR) by controlling m6A modification of SOX2 mRNA. METTL3 upregulation protects against high glucose-induced damage in retinal cells, suggesting a therapeutic target for DR.
Area of Science:
- Ophthalmology
- Molecular Biology
- Epigenetics
Background:
- Diabetic retinopathy (DR) is a significant complication of diabetes.
- The role of RNA modifications in DR pathogenesis is increasingly recognized.
- Methyltransferase-like 3 (METTL3) is a key m6A RNA methyltransferase.
Purpose of the Study:
- To investigate the regulatory role of METTL3 in DR.
- To explore METTL3's mechanism involving SOX2 mRNA m6A modification.
- To elucidate the molecular pathways underlying METTL3's effects on retinal cells.
Main Methods:
- Established a diabetic retinopathy (DR) model using high glucose (HG)-stimulated human retinal endothelial cells (HRECs).
- Quantified METTL3, IGF2BP2, and SOX2 expression via qRT-PCR and Western blotting.
- Utilized RNA-binding protein immunoprecipitation (RIP) to confirm molecular interactions.
- Assessed HREC proliferation (MTT) and apoptosis (flow cytometry, Western blotting for cleaved-caspase3).
Main Results:
- METTL3, IGF2BP2, and SOX2 expression were decreased in DR patients' sera and HG-treated HRECs.
- RIP confirmed the interaction between METTL3 and SOX2 mRNA.
- HG treatment impaired HREC viability, increased apoptosis, and elevated cleaved-caspase3 levels.
- METTL3 upregulation rescued HG-induced cellular damage, while SOX2 knockdown partially reversed METTL3's protective effects.
Conclusions:
- METTL3 plays a protective role in diabetic retinopathy.
- METTL3 regulates DR progression by modulating m6A modification of SOX2 mRNA.
- METTL3 represents a potential therapeutic target for managing diabetic retinopathy.
