Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease
Abstract H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) remain elusive. Here, a genome‐wide comparative study on H3K27ac activities and tr...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404224 |
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| author | Yaling Zhu Limeng Shang Yunshu Tang Qiushuang Li Lin Ding Yi Wang Tiantian Zhang Bin Xie Jinhu Ma Xinyu Li Shuwen Chen Xinrui Yi Jin Peng Youfeng Liang Anyuan He Hong Yan Huaqing Zhu Buchun Zhang Yong Zhu |
| author_facet | Yaling Zhu Limeng Shang Yunshu Tang Qiushuang Li Lin Ding Yi Wang Tiantian Zhang Bin Xie Jinhu Ma Xinyu Li Shuwen Chen Xinrui Yi Jin Peng Youfeng Liang Anyuan He Hong Yan Huaqing Zhu Buchun Zhang Yong Zhu |
| author_sort | Yaling Zhu |
| collection | DOAJ |
| description | Abstract H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) remain elusive. Here, a genome‐wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)‐induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP‐Seq and RNA‐Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1‐promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF‐κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs‐Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs‐Allo robustly alleviates HFD‐induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac‐TDO2‐NF‐κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment. |
| format | Article |
| id | doaj-art-4e981dda2f524e64b6e8d4f25f3b76cd |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4e981dda2f524e64b6e8d4f25f3b76cd2024-12-04T12:14:55ZengWileyAdvanced Science2198-38442024-12-011145n/an/a10.1002/advs.202404224Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver DiseaseYaling Zhu0Limeng Shang1Yunshu Tang2Qiushuang Li3Lin Ding4Yi Wang5Tiantian Zhang6Bin Xie7Jinhu Ma8Xinyu Li9Shuwen Chen10Xinrui Yi11Jin Peng12Youfeng Liang13Anyuan He14Hong Yan15Huaqing Zhu16Buchun Zhang17Yong Zhu18Department of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaLaboratory Animal Research Center School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Cardiology The First Affiliated Hospital of Anhui Medical University Hefei Anhui 230001 ChinaSchool of Life Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Pathology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaLaboratory of Molecular Biology and Department of Biochemistry Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Cardiology The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaDepartment of Pathophysiology School of Basic Medical Sciences Anhui Medical University Hefei Anhui 230032 ChinaAbstract H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) remain elusive. Here, a genome‐wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)‐induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP‐Seq and RNA‐Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1‐promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF‐κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs‐Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs‐Allo robustly alleviates HFD‐induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac‐TDO2‐NF‐κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment.https://doi.org/10.1002/advs.202404224H3K27acM1 polarizationMASLDTDO2YY1 |
| spellingShingle | Yaling Zhu Limeng Shang Yunshu Tang Qiushuang Li Lin Ding Yi Wang Tiantian Zhang Bin Xie Jinhu Ma Xinyu Li Shuwen Chen Xinrui Yi Jin Peng Youfeng Liang Anyuan He Hong Yan Huaqing Zhu Buchun Zhang Yong Zhu Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease Advanced Science H3K27ac M1 polarization MASLD TDO2 YY1 |
| title | Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease |
| title_full | Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease |
| title_fullStr | Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease |
| title_full_unstemmed | Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease |
| title_short | Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease |
| title_sort | genome wide profiling of h3k27ac identifies tdo2 as a pivotal therapeutic target in metabolic associated steatohepatitis liver disease |
| topic | H3K27ac M1 polarization MASLD TDO2 YY1 |
| url | https://doi.org/10.1002/advs.202404224 |
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