KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression
Abstract Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed i...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00373-1 |
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| author | Ouqiang Wu Yuxin Jin Zhiguang Zhang Hao Zhou Wenbin Xu Linjie Chen Morgan Jones Kenny Yat Hong Kwan Jianyuan Gao Kai Zhang Xiaofei Cheng Qizhu Chen Xinzhou Wang Yan Michael Li Zhenyu Guo Jing Sun Zhihua Chen Bin Wang Xiangyang Wang Shuying Shen Aimin Wu |
| author_facet | Ouqiang Wu Yuxin Jin Zhiguang Zhang Hao Zhou Wenbin Xu Linjie Chen Morgan Jones Kenny Yat Hong Kwan Jianyuan Gao Kai Zhang Xiaofei Cheng Qizhu Chen Xinzhou Wang Yan Michael Li Zhenyu Guo Jing Sun Zhihua Chen Bin Wang Xiangyang Wang Shuying Shen Aimin Wu |
| author_sort | Ouqiang Wu |
| collection | DOAJ |
| description | Abstract Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(m6A)-methylated modification regulates autophagy in IVDD-NPCs. Mechanistically, lysine methyltransferase 2A (KMT2A) promoted the expression of methyltransferase-like 3 (METTL3) through H3K4me3 modification, whereas METTL3-mediated m6A modification reduced the expression of autophagy-associated 4a (ATG4a) by attenuating its RNA stability, leading to autophagy damage in NPCs. Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs. Therefore, targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD. |
| format | Article |
| id | doaj-art-a1ae1677cbfa4535b644c1c17ef8627a |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-a1ae1677cbfa4535b644c1c17ef8627a2024-11-24T12:14:46ZengNature Publishing GroupBone Research2095-62312024-11-0112111810.1038/s41413-024-00373-1KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progressionOuqiang Wu0Yuxin Jin1Zhiguang Zhang2Hao Zhou3Wenbin Xu4Linjie Chen5Morgan Jones6Kenny Yat Hong Kwan7Jianyuan Gao8Kai Zhang9Xiaofei Cheng10Qizhu Chen11Xinzhou Wang12Yan Michael Li13Zhenyu Guo14Jing Sun15Zhihua Chen16Bin Wang17Xiangyang Wang18Shuying Shen19Aimin Wu20Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Emergency Medicine Center, Jinhua Municipal Central HospitalDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversitySpine Unit, The Royal Orthopaedic Hospital, Bristol Road South, NorthfieldDepartment of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong KongDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityShanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Neurosurgery, University of Rochester Medical CenterDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityAbstract Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(m6A)-methylated modification regulates autophagy in IVDD-NPCs. Mechanistically, lysine methyltransferase 2A (KMT2A) promoted the expression of methyltransferase-like 3 (METTL3) through H3K4me3 modification, whereas METTL3-mediated m6A modification reduced the expression of autophagy-associated 4a (ATG4a) by attenuating its RNA stability, leading to autophagy damage in NPCs. Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs. Therefore, targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.https://doi.org/10.1038/s41413-024-00373-1 |
| spellingShingle | Ouqiang Wu Yuxin Jin Zhiguang Zhang Hao Zhou Wenbin Xu Linjie Chen Morgan Jones Kenny Yat Hong Kwan Jianyuan Gao Kai Zhang Xiaofei Cheng Qizhu Chen Xinzhou Wang Yan Michael Li Zhenyu Guo Jing Sun Zhihua Chen Bin Wang Xiangyang Wang Shuying Shen Aimin Wu KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression Bone Research |
| title | KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression |
| title_full | KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression |
| title_fullStr | KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression |
| title_full_unstemmed | KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression |
| title_short | KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression |
| title_sort | kmt2a regulates the autophagy gata4 axis through mettl3 mediated m6a modification of atg4a to promote npcs senescence and ivdd progression |
| url | https://doi.org/10.1038/s41413-024-00373-1 |
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