PUBLICATION
Activation of prep expression by Tet2 promotes the proliferation of bipotential progenitor cells during liver regeneration
- Authors
- Jia, K., Cheng, B., Huang, L., Xu, J., Liu, F., Liao, X., Liao, K., Lu, H.
- ID
- ZDB-PUB-250221-3
- Date
- 2025
- Source
- Development (Cambridge, England) : (Journal)
- Registered Authors
- Lu, Huiqiang
- Keywords
- Biliary epithelial cells, DNA demethylation, PI3K-AKT-mTOR pathway, Proliferation, Prolyl endopeptidase, Ten-eleven translocation 2
- MeSH Terms
-
- Zebrafish*
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Stem Cells*/cytology
- Stem Cells*/metabolism
- Cell Proliferation*/genetics
- Serine Endopeptidases/genetics
- Serine Endopeptidases/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- DNA Methylation/genetics
- Animals
- Epithelial Cells/cytology
- Epithelial Cells/metabolism
- Liver/cytology
- Liver/metabolism
- Promoter Regions, Genetic/genetics
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Dioxygenases*/genetics
- Dioxygenases*/metabolism
- Liver Regeneration*/genetics
- Signal Transduction
- Phosphatidylinositol 3-Kinases/metabolism
- PubMed
- 39976298 Full text @ Development
Citation
Jia, K., Cheng, B., Huang, L., Xu, J., Liu, F., Liao, X., Liao, K., Lu, H. (2025) Activation of prep expression by Tet2 promotes the proliferation of bipotential progenitor cells during liver regeneration. Development (Cambridge, England). :.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping