Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming
Abstract Matrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HS...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08160-2 |
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| _version_ | 1849691325528539136 |
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| author | Wenxue Zhao Weihong Yuan Tian Dong Wei Qi Zhijie Feng Cheng Li Yujie Sun |
| author_facet | Wenxue Zhao Weihong Yuan Tian Dong Wei Qi Zhijie Feng Cheng Li Yujie Sun |
| author_sort | Wenxue Zhao |
| collection | DOAJ |
| description | Abstract Matrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches. |
| format | Article |
| id | doaj-art-5477ad0aca5a4f199abd96b5d3d9af8f |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-5477ad0aca5a4f199abd96b5d3d9af8f2025-08-20T03:21:03ZengNature PortfolioCommunications Biology2399-36422025-06-018111710.1038/s42003-025-08160-2Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin primingWenxue Zhao0Weihong Yuan1Tian Dong2Wei Qi3Zhijie Feng4Cheng Li5Yujie Sun6School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking UniversitySchool of Life Sciences, Peking UniversitySchool of Life Sciences, Peking UniversityDepartment of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive DiseasesDepartment of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive DiseasesSchool of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking UniversityBiomedical Pioneering Innovation Center (BIOPIC), Peking UniversityAbstract Matrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches.https://doi.org/10.1038/s42003-025-08160-2 |
| spellingShingle | Wenxue Zhao Weihong Yuan Tian Dong Wei Qi Zhijie Feng Cheng Li Yujie Sun Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming Communications Biology |
| title | Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming |
| title_full | Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming |
| title_fullStr | Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming |
| title_full_unstemmed | Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming |
| title_short | Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming |
| title_sort | increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through ap 1 induced chromatin priming |
| url | https://doi.org/10.1038/s42003-025-08160-2 |
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