A Positive Feedback Loop of TET3 and TGF-β1 Promotes Liver Fibrosis
Open accessAbstract
Pathological activation of TGF-β signaling is universal in fibrosis. Aberrant TGF-β signaling in conjunction with transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts plays a central role in liver fibrosis. Here we report that the DNA demethylase TET3 is anomalously upregulated in fibrotic livers in both humans and mice. We demonstrate that in human HSCs, TET3 promotes profibrotic gene expression by upregulation of multiple key TGF-β pathway genes, including TGFB1. TET3 binds to target gene promoters, inducing demethylation, which in turn facilitates chromatin remodeling and transcription. We also reveal a positive feedback loop between TGF-β1 and TET3 in both HSCs and hepatocytes. Furthermore, TET3 knockdown ameliorates liver fibrosis in mice. Our results uncover a TET3/TGF-β1 positive feedback loop as a crucial determinant of liver fibrosis and suggest that inhibiting TET3 may represent a therapeutic strategy for liver fibrosis and perhaps other fibrotic diseases.
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Other epigenetic regulators, including MECP2, EZH1/2, BRD4, SIRT1, KDM4D, and TET3, can contribute to chemically induced liver fibrosis.
“Other epigenetic regulators, such as methyl CpG binding protein 2 (MECP2), enhancer of zeste homolog 1/2 (EZH1/2), bromodomain-containing protein 4 (BRD4), Sirtuin 1 (SIRT1), lysine-specific demethylase 4D (KDM4D), and tet methylcytosine dioxygenase 3 (TET3), can contribute to chemically-induced liver fibrosis (174-178) (179, 180) (181).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [181]
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- Authors
- Xu, Y., Sun, X., Zhang, R., Cao, T., Cai, S.-Y., Boyer, J. L., Zhang, X., Li, D., & Huang, Y.
- Affiliations
- Yale University (US)
- Nantong University (CN)
- Shanghai Jiao Tong University (CN)
- Sheng Jing Hospital (CN)
- Corresponding author
- Li, Da
- Huang, Yingqun
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 5
- Pages
- 1310-1318.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7063678
- OpenAlex
- W3005492466
- Cited by
- 73
- References
- 32
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 7 · 2023: 17 · 2022: 16 · 2021: 13 · 2020: 5
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- TET3, TGF-β1, liver fibrosis, hepatic stellate cells, DNA demethylation, positive feedback loop, chromatin remodeling, transcriptional regulation, myofibroblast transdifferentiation, hepatocytes
- MeSH terms
- Adult, Animals, Base Sequence, Cell Line, Female, Humans, Liver Cirrhosis, Male, Mice, Inbred C57BL, Middle Aged, Signal Transduction, Up-Regulation, Hepatocytes, Feedback, Physiological, Epigenesis, Genetic, Dioxygenases, Transforming Growth Factor beta1, Hepatic Stellate Cells
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