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METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial–mesenchymal transition
Yuwei Wang1,2,† , Yuhong Chen1,2,† , Jian Liang2,† , Mei Jiang1,2 , Ting Zhang1,2 , Xiaoling Wan1,2 , Jiahui Wu1,2 , Xiaomeng Li1,2 , Jieqiong Chen1,2 , Junran Sun1,2 , Yifan Hu1,2 , Peirong Huang1,2 , Jingyang Feng1,2 , Te Liu3,* , Xiaodong Sun1,2,4,5,*
1Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
2Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
3Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China
4National Clinical Research Center for Eye Diseases, Shanghai 200080, China
5Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
†These authors contributed equally to this work
*Correspondence to:Te Liu , Email:liute1979@shutcm.edu.cn Xiaodong Sun , Email:xdsun@sjtu.edu.cn
J Mol Cell Biol, Volume 15, Issue 3, March 2023, mjad005,  https://doi.org/10.1093/jmcb/mjad005
Keyword: METTL3, N6-methyladenosine, epithelial–mesenchymal transition, subretinal fibrosis, HMGA2

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.


Volume 15, Issue 3
March 2023