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
{"title":"METTL3介导的HMGA2mRNA的m6A修饰促进视网膜下纤维化和上皮-间质转化。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603769/pdf/","citationCount":"4","resultStr":"{\"title\":\"METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":16433,\"journal\":{\"name\":\"Journal of Molecular Cell Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2023-08-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603769/pdf/\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1093/jmcb/mjad005\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/jmcb/mjad005","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition.
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.
期刊介绍：
The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome.
JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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