DNMT3a-mediated methylation of TCF21/hnRNPA1 aggravates hepatic fibrosis by regulating the NF-κB signaling pathway
Liang‐yun Li, Shaoxi Diao, Zixiang Chen, Jintong Zhang, Wei J. Chen, Tianqi Wang, Xin Chen, Yuxin Zhao, Tao Xu, Cheng Huang, Jun Li
Abstract
Hepatic fibrosis is caused by liver damage as a consequence of wound healing response. Recent studies have shown that hepatic fibrosis could be effectively reversed, partly through regression of activated hepatic stellate cells (HSCs). Transcription factor 21 (TCF21), a member of the basic helix-loop-helix (bHLH) transcription factor, is involved in epithelial-mesenchymal transformation in various diseases. However, the mechanism by which TCF21 regulates epithelial-mesenchymal transformation in hepatic fibrosis has not been elucidated. In this research, we found that hnRNPA1, the downstream binding protein of TCF21, accelerates hepatic fibrosis reversal by inhibiting the NF-κB signaling pathway. Furthermore, the combination of DNMT3a with TCF21 promoter results in TCF21 hypermethylation. Our results suggest that DNMT3a regulation of TCF21 is a significant event in reversing hepatic fibrosis. In conclusion, this research identifies a novel signaling axis, DNMT3a-TCF21-hnRNPA1, that regulates HSCs activation and hepatic fibrosis reversal, providing a novel treatment strategy for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry9079).