ABSTRACT
Biliary epithelial cell (BEC)-derived liver regeneration in zebrafish exhibits similarities to liver regeneration in chronic liver injury. However, the underlying mechanisms remain poorly understood. Here, we identified a serine peptidase called prolyl endopeptidase (Prep) as an indispensable factor during the BEC-derived liver regeneration process. prep was significantly upregulated and enriched in bipotential progenitor cells (BP-PCs). Through gain- and loss-of-function assays, prep was found to potently accelerate liver regeneration and drastically increase the proliferation of BP-PCs. Mechanistically, prep expression was directly regulated by ten-eleven translocation 2 (Tet2)-mediated DNA demethylation. More strikingly, Tet2 regulated prep expression by directly interacting and reducing the methylation of CpG sites in the prep promoter. Subsequently, Prep activated the PI3K-AKT-mTOR signaling pathway to regulate liver regeneration. Therefore, our study revealed the role and mechanism of Tet2-mediated DNA demethylation-associated upregulation of prep in the proliferation of BP-PCs during liver regeneration. These results identify promising targets for stimulating regeneration following chronic liver injury.
Footnotes
Author contributions
Conceptualization: K.L., H.L.; Data curation: K.J.; Formal analysis: K.L.; Funding acquisition: H.L.; Investigation: K.J., B.C., L.H., J.X., F.L.; Methodology: K.J., B.C., L.H., K.L.; Project administration: H.L.; Resources: K.L., H.L.; Software: K.J., L.H.; Supervision: K.J., B.C., H.L.; Visualization: K.J., K.L.; Writing – original draft: K.J.; Writing – review & editing: X.L., H.L.
Funding
This work was supported by the National Key Research and Development Program of China (2018YFA0801000), National Natural Science Foundation of China (81560109, 31771606 and 32170853), Natural Science Foundation of Jiangxi Province (2018ABC21033) and Science and Technology Foundation of the Education Department of Jiangxi Province (GJJ201002).
Data availability
All relevant data can be found within the article and its supplementary information.
