A Positive Feedback Loop of TET3 and TGF-β1 Promotes Liver Fibrosis
Yetao Xu,
Xiaoli Sun,
Ruling Zhang,
Tiefeng Cao,
Shi-Ying Cai,
James L. Boyer,
Xuchen Zhang,
Da Li,
Yingqun Huang
Affiliations
Yetao Xu
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Center of Reproductive Medicine, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu 211166, China
Xiaoli Sun
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Jiangsu 226001, China
Ruling Zhang
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
Tiefeng Cao
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Gynecology and Obstetrics, First Affiliated Hospital of Sun Yat-Sen University, Guangdong 510070, China
Shi-Ying Cai
Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
James L. Boyer
Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
Xuchen Zhang
Pathology Department, Yale University School of Medicine, New Haven, CT 06510, USA
Da Li
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China; Corresponding author
Yingqun Huang
Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA; Corresponding author
Summary: 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. : Xu et al. unmask a positive feedback loop between chromatin demethylase TET3 and TGF-β1 in stressed hepatocytes and stellate cells in humans and mice. Activation of this loop stimulates expression of fibrotic genes, whereas knockdown of TET3 reduces liver fibrosis in mice, suggesting a strategy for treating fibrosis.
