METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition
Yuwei Wang1,2, Yuhong Chen1,2, Jian Liang2
1Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Abstract:
Subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration (nAMD). Myofibroblasts originated from retinal pigment epithelial (RPE) cells through epithelial-mesenchymal transition (EMT) contribute to the fibrosis formation. N6-Methyladenosine (m6A) modification has been implicated in the EMT process and multiple fibrotic diseases. The role of m6A modification in EMT-related subretinal fibrosis has not yet been elucidated. In this study, we found that during subretinal fibrosis in the mouse model of laser-induced choroidal neovascularization, METTL3 was upregulated in RPE cells. Through m6A epitranscriptomic microarray and further verification, high-mobility group AT-hook 2 (HMGA2) was identified as the key downstream target of METTL3, subsequently activating potent EMT-inducing transcription factor SNAIL. Finally, by subretinal injections of adeno-associated virus vectors, we confirmed that METTL3 deficiency in RPE cells could efficiently attenuate subretinal fibrosis in vivo. In conclusion, our present research identified an epigenetic mechanism of METTL3-m6A-HMGA2 in subretinal fibrosis and EMT of RPE cells, providing a novel therapeutic target for subretinal fibrosis secondary to nAMD.
Insights
Researchers identified METTL3 as a key factor in subretinal fibrosis, a complication of neovascular age-related macular degeneration (nAMD). Targeting METTL3 may offer a new therapeutic strategy for nAMD patients experiencing vision loss.
Area of Science:
- Ophthalmology
- Epigenetics
- Cell Biology
Background:
- Subretinal fibrosis significantly impairs vision in neovascular age-related macular degeneration (nAMD).
- Retinal pigment epithelial (RPE) cells undergoing epithelial-mesenchymal transition (EMT) are a primary source of myofibroblasts driving fibrosis.
- N6-Methyladenosine (m6A) modification is implicated in EMT and fibrotic diseases, but its role in RPE-related fibrosis is unknown.
Purpose of the Study:
- To investigate the role of m6A modification, specifically METTL3, in RPE cell EMT and subretinal fibrosis.
- To identify downstream targets of METTL3 involved in the fibrotic process.
- To evaluate METTL3 as a potential therapeutic target for nAMD-associated subretinal fibrosis.
Main Methods:
- Utilized a laser-induced choroidal neovascularization mouse model to study subretinal fibrosis.
- Assessed METTL3 expression in RPE cells during fibrosis development.
- Employed m6A epitranscriptomic microarray to identify downstream targets.
- Verified the METTL3-HMGA2-SNAIL signaling pathway.
- Used adeno-associated virus vectors for in vivo gene manipulation (METTL3 deficiency).
Main Results:
- METTL3 expression was upregulated in RPE cells during subretinal fibrosis.
- High-mobility group AT-hook 2 (HMGA2) was identified as a direct downstream target of METTL3.
- METTL3-mediated HMGA2 activation led to the upregulation of SNAIL, a potent EMT inducer.
- Genetic deficiency of METTL3 in RPE cells significantly attenuated subretinal fibrosis in vivo.
Conclusions:
- An epigenetic mechanism involving METTL3-m6A modification, HMGA2, and SNAIL drives RPE cell EMT and subretinal fibrosis.
- METTL3 plays a critical role in the pathogenesis of subretinal fibrosis.
- Targeting the METTL3-m6A pathway presents a promising therapeutic strategy for subretinal fibrosis in nAMD.
