The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases
Abstract The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer
2024-01-01
|
| Series: | Molecular Biomedicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43556-023-00161-z |
| _version_ | 1797363733500002304 |
|---|---|
| author | Min Tao Yingfeng Shi Hui Chen Jinqing Li Yi Wang Xiaoyan Ma Lin Du Yishu Wang Xinyu Yang Yan Hu Xun Zhou Qin Zhong Danying Yan Andong Qiu Shougang Zhuang Na Liu |
| author_facet | Min Tao Yingfeng Shi Hui Chen Jinqing Li Yi Wang Xiaoyan Ma Lin Du Yishu Wang Xinyu Yang Yan Hu Xun Zhou Qin Zhong Danying Yan Andong Qiu Shougang Zhuang Na Liu |
| author_sort | Min Tao |
| collection | DOAJ |
| description | Abstract The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential. |
| first_indexed | 2024-03-08T16:25:23Z |
| format | Article |
| id | doaj.art-663f44a745d44c06ba98b3ce59acfa26 |
| institution | Directory Open Access Journal |
| issn | 2662-8651 |
| language | English |
| last_indexed | 2024-03-08T16:25:23Z |
| publishDate | 2024-01-01 |
| publisher | Springer |
| record_format | Article |
| series | Molecular Biomedicine |
| spelling | doaj.art-663f44a745d44c06ba98b3ce59acfa262024-01-07T12:04:40ZengSpringerMolecular Biomedicine2662-86512024-01-015111610.1186/s43556-023-00161-zThe disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinasesMin Tao0Yingfeng Shi1Hui Chen2Jinqing Li3Yi Wang4Xiaoyan Ma5Lin Du6Yishu Wang7Xinyu Yang8Yan Hu9Xun Zhou10Qin Zhong11Danying Yan12Andong Qiu13Shougang Zhuang14Na Liu15Department of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineShanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji UniversityDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineDepartment of Nephrology, Pudong New District, Shanghai East Hospital, Tongji University School of MedicineAbstract The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential.https://doi.org/10.1186/s43556-023-00161-zDisruptor of telomeric silencing 1-likeDi-methylation of histone H3 on lysine-79Epidermal growth factor receptorJanus kinase 3Peritoneal fibrosis |
| spellingShingle | Min Tao Yingfeng Shi Hui Chen Jinqing Li Yi Wang Xiaoyan Ma Lin Du Yishu Wang Xinyu Yang Yan Hu Xun Zhou Qin Zhong Danying Yan Andong Qiu Shougang Zhuang Na Liu The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases Molecular Biomedicine Disruptor of telomeric silencing 1-like Di-methylation of histone H3 on lysine-79 Epidermal growth factor receptor Janus kinase 3 Peritoneal fibrosis |
| title | The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| title_full | The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| title_fullStr | The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| title_full_unstemmed | The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| title_short | The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| title_sort | disruptor of telomeric silencing 1 like dot1l promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases |
| topic | Disruptor of telomeric silencing 1-like Di-methylation of histone H3 on lysine-79 Epidermal growth factor receptor Janus kinase 3 Peritoneal fibrosis |
| url | https://doi.org/10.1186/s43556-023-00161-z |
| work_keys_str_mv | AT mintao thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yingfengshi thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT huichen thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT jinqingli thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yiwang thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xiaoyanma thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT lindu thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yishuwang thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xinyuyang thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yanhu thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xunzhou thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT qinzhong thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT danyingyan thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT andongqiu thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT shougangzhuang thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT naliu thedisruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT mintao disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yingfengshi disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT huichen disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT jinqingli disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yiwang disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xiaoyanma disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT lindu disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yishuwang disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xinyuyang disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT yanhu disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT xunzhou disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT qinzhong disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT danyingyan disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT andongqiu disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT shougangzhuang disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases AT naliu disruptoroftelomericsilencing1likedot1lpromotesperitonealfibrosisthroughtheupregulationandactivationofproteintyrosinekinases |