METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition

Yuwei Wang; Yuhong Chen; Jian Liang; Mei Jiang; Ting Zhang; Xiaoling Wan; Jiahui Wu; Xiaomeng Li; Jieqiong Chen; Junran Sun; Yifan Hu; Peirong Huang; Jingyang Feng; Te Liu; Xiaodong Sun

doi:10.1093/jmcb/mjad005

METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition

J Mol Cell Biol. 2023 Aug 3;15(3):mjad005. doi: 10.1093/jmcb/mjad005.

Authors

Yuwei Wang^{1

2}, Yuhong Chen^{1

2}, Jian Liang², Mei Jiang^{1

2}, Ting Zhang^{1

2}, Xiaoling Wan^{1

2}, Jiahui Wu^{1

2}, Xiaomeng Li^{1

2}, Jieqiong Chen^{1

2}, Junran Sun^{1

2}, Yifan Hu^{1

2}, Peirong Huang^{1

2}, Jingyang Feng^{1

2}, Te Liu³, Xiaodong Sun^{1

2

4

5}

Affiliations

¹ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
² Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China.
³ Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
⁴ National Clinical Research Center for Eye Diseases, Shanghai 200080, China.
⁵ Shanghai Engineering Center for Visual Science and Photomedicine, 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.

Keywords: N 6-methyladenosine; HMGA2; METTL3; epithelial–mesenchymal transition; subretinal fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epithelial-Mesenchymal Transition* / genetics
Fibrosis
HMGA2 Protein
Humans
Methyltransferases* / genetics
Mice
RNA, Messenger / genetics
Transcription Factors

Substances

Methyltransferases
METTL3 protein, human
RNA, Messenger
Transcription Factors
Mettl3 protein, mouse
HMGA2 Protein