A Positive Feedback Loop of TET3 and TGF-β1 Promotes Liver Fibrosis

Abstract

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.