m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells
Abstract Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysi...
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BMC
2024-11-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-024-03279-1 |
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| author | Qian Zhou Xianyang Liu Huiping Lu Na Li Jiayu Meng Jiaxing Huang Zhi Zhang Jiangyi Liu Wei Fan Wanqian Li Xingran Li Xiaoyan Liu Hangjia Zuo Peizeng Yang Shengping Hou |
| author_facet | Qian Zhou Xianyang Liu Huiping Lu Na Li Jiayu Meng Jiaxing Huang Zhi Zhang Jiangyi Liu Wei Fan Wanqian Li Xingran Li Xiaoyan Liu Hangjia Zuo Peizeng Yang Shengping Hou |
| author_sort | Qian Zhou |
| collection | DOAJ |
| description | Abstract Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysis revealed that retinal pigment epithelium (RPE) cells serve a crucial promotional function in angiogenesis. RPE cells were regulated by N6-methyladenosine (m6A). Next, we detected several critical m6A methylase in hypoxic ARPE-19 cells and in oxygen-induced retinopathy (OIR) mice, our results revealed a significant decrease in the level of methyltransferase like 3 (METTL3). METTL3 specific inhibitor STM2457 intravitreal injection or METTL3 conditional knockout mice both showed a significantly reduced neovascularization area of retina. Additionally, the angiogenesis-related abilities of human retinal endothelial cells (HRECs) were diminished after co-cultured with ARPE-19 treated with STM2457 or sh-METTL3 in vitro. Furthermore, through the integration of Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing, we discovered that the metabolic enzyme quinolinate phosphoribosyltransferase (QPRT) was directly modified by METTL3 and recognized by the YTH N6-methyladenosine RNA binding protein C1 (YTHDC1). Moreover, after over-expressing QPRT, the angiogenic abilities of HRECs were improved through the phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/ phosphorylated threonine kinase (p-AKT) pathway. Collectively, our study provided a novel therapeutic target for retinal angiogenesis. |
| format | Article |
| id | doaj-art-4efaaede73cd4a619f0a6e11bb846fb1 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-4efaaede73cd4a619f0a6e11bb846fb12025-08-20T02:13:26ZengBMCJournal of Neuroinflammation1742-20942024-11-0121111510.1186/s12974-024-03279-1m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cellsQian Zhou0Xianyang Liu1Huiping Lu2Na Li3Jiayu Meng4Jiaxing Huang5Zhi Zhang6Jiangyi Liu7Wei Fan8Wanqian Li9Xingran Li10Xiaoyan Liu11Hangjia Zuo12Peizeng Yang13Shengping Hou14The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesBeijing Tongren Hospital, Capital Medical UniversitySichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesThe First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular DiseasesAbstract Retinal neovascularization (RNV) disease is one of the leading causes of blindness, yet the molecular underpinnings of this condition are not well understood. To delve into the critical aspects of cell-mediated angiogenesis, we analyzed our previously published single-cell data. Our analysis revealed that retinal pigment epithelium (RPE) cells serve a crucial promotional function in angiogenesis. RPE cells were regulated by N6-methyladenosine (m6A). Next, we detected several critical m6A methylase in hypoxic ARPE-19 cells and in oxygen-induced retinopathy (OIR) mice, our results revealed a significant decrease in the level of methyltransferase like 3 (METTL3). METTL3 specific inhibitor STM2457 intravitreal injection or METTL3 conditional knockout mice both showed a significantly reduced neovascularization area of retina. Additionally, the angiogenesis-related abilities of human retinal endothelial cells (HRECs) were diminished after co-cultured with ARPE-19 treated with STM2457 or sh-METTL3 in vitro. Furthermore, through the integration of Methylated RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing, we discovered that the metabolic enzyme quinolinate phosphoribosyltransferase (QPRT) was directly modified by METTL3 and recognized by the YTH N6-methyladenosine RNA binding protein C1 (YTHDC1). Moreover, after over-expressing QPRT, the angiogenic abilities of HRECs were improved through the phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/ phosphorylated threonine kinase (p-AKT) pathway. Collectively, our study provided a novel therapeutic target for retinal angiogenesis.https://doi.org/10.1186/s12974-024-03279-1Retinal neovascularizationRetinal pigment epitheliumMethyltransferase like 3Quinolinate phosphoribosyltransferasep-PI3K/p-AKT pathway |
| spellingShingle | Qian Zhou Xianyang Liu Huiping Lu Na Li Jiayu Meng Jiaxing Huang Zhi Zhang Jiangyi Liu Wei Fan Wanqian Li Xingran Li Xiaoyan Liu Hangjia Zuo Peizeng Yang Shengping Hou m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells Journal of Neuroinflammation Retinal neovascularization Retinal pigment epithelium Methyltransferase like 3 Quinolinate phosphoribosyltransferase p-PI3K/p-AKT pathway |
| title | m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells |
| title_full | m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells |
| title_fullStr | m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells |
| title_full_unstemmed | m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells |
| title_short | m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells |
| title_sort | m6a methylase mettl3 promotes retinal angiogenesis through modulation of metabolic reprogramming in rpe cells |
| topic | Retinal neovascularization Retinal pigment epithelium Methyltransferase like 3 Quinolinate phosphoribosyltransferase p-PI3K/p-AKT pathway |
| url | https://doi.org/10.1186/s12974-024-03279-1 |
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