TET1 inhibits liver fibrosis by blocking hepatic stellate cell activation
Jingjie Wang
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Co-first author: Jingjie Wang, Yitong ZhangSearch for more papers by this authorYitong Zhang
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Co-first author: Jingjie Wang, Yitong ZhangSearch for more papers by this authorYanyun Ma
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
Six-sector Industrial Research Institute, Fudan University, Shanghai, China
Search for more papers by this authorSuhan Zhao
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorJiucun Wang
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Hongtan Chen
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jun Zhang
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jie Liu
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorJingjie Wang
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Co-first author: Jingjie Wang, Yitong ZhangSearch for more papers by this authorYitong Zhang
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Co-first author: Jingjie Wang, Yitong ZhangSearch for more papers by this authorYanyun Ma
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
Six-sector Industrial Research Institute, Fudan University, Shanghai, China
Search for more papers by this authorSuhan Zhao
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Search for more papers by this authorJiucun Wang
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China
Search for more papers by this authorCorresponding Author
Hongtan Chen
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jun Zhang
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jie Liu
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
Correspondence
Jie Liu, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai 201203, China.
Email: [email protected]
Jun Zhang, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Email: [email protected]
Hongtan Chen, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou,310002, China.
Email: [email protected]
Search for more papers by this authorDeclaration of conflict of interest: No conflict of interest is declared in the submission of this manuscript.
Abstract
Hepatic stellate cells (HSCs) are critical regulator contributing to the onset and progression of liver fibrosis. Chronic liver injury triggers HSCs to undergo vast changes and trans-differentiation into a myofibroblast HSCs, the mechanism remains to be elucidated. This study investigated that the involvement of hydroxymethylase TET1 (ten–eleven translocation 1) in HSC activation and liver fibrosis. It is revealed that TET1 levels were downregulated in the livers in mouse models of liver fibrosis and patients with cirrhosis, as well as activated HSCs in comparison to quiescent HSCs. In vitro data showed that the inhibition of TET1 promoted the activation HSC, whereas TET1 overexpression inhibited HSC activation. Moreover, TET1 could regulate KLF2 (Kruppel-like transcription factors) transcription by promoting hydroxymethylation of its promoter, which in turn suppressed the activation of HSCs. In vivo, it is confirmed that liver fibrosis was aggravated in Tet1 knockout mice after CCl4 injection, accompanied by excessive activation of primary stellate cells, in contrast to wild-type mice. In conclusion, we suggested that TET1 plays a significant role in HSC activation and liver fibrosis, which provides a promising target for anti-fibrotic therapies.
Graphical Abstract
Supporting Information
| Filename | Description |
|---|---|
| jgh16443-sup-0001-Supplementary.docxWord 2007 document , 350.1 KB |
Table S1. Primers' sequences for ChIP. Table S2. Primers' sequences for knockdown of negative control, TET1 and Smad3. Table S3. Primers' sequences for quantification of relative genes in real time PCR. |
| jgh16443-sup-0002-SUPPLEMENTARY FIG 1.tifTIFF image, 2.3 MB |
Figure S1. TET1 promotes the apoptosis of HSCs. A) The apoptosis rate of LX-2 transfected with TET1 overexpression plasmids. B) The expression of cleaved caspase-3 was examined by Western Blot. |
| jgh16443-sup-0003-SUPPLEMENTARY FIG2.tifTIFF image, 3.1 MB |
Figure S2. KLF2 inhibits HSCs activation. A) The KLF2 expression level after TGF-β treatment in LX-2 cells. B,C) The mRNA levels of fibrotic genes in LX-2 cells transfected with KLF2 overexpression plasmids. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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