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

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外文摘要：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 m6Aepitranscriptomic 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.

外文关键词：

METTL3N6-methyladenosineepithelial-mesenchymal transitionsubretinal fibrosisHMGA2

作者：

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

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作者单位：

Department of Ophthalmology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China

Shanghai Key Laboratory of Ocular Fundus Diseases,Shanghai 200080,China

Shanghai Geriatric Institute of Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200031,China

National Clinical Research Center for Eye Diseases,Shanghai 200080,China

Shanghai Engineering Center for Visual Science and Photomedicine,Shanghai 200080,China

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基金：

National Natural Science Foundation of ChinaNational Key Technologies R&D ProgramShanghai Hospital Development CenterShanghai Hospital Development Center

项目编号：

817300262017YFA0105301SHDC2020CR2040BSHDC2020CR5014

出版年：

2023

DOI：

10.1093/jmcb/mjad005

分子细胞生物学报(英文版)

中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD

影响因子：0.595

ISSN：1673-520X

年,卷(期)：2023.15(3)

参考文献量65