PUBLICATION
Rngtt governs biliary-derived liver regeneration initiation by transcriptional regulation of mTORC1 and Dnmt1 in zebrafish
- Authors
- Ma, J., Yang, Z., Huang, Z., Li, L., Huang, J., Chen, J., Ni, R., Luo, L., He, J.
- ID
- ZDB-PUB-230202-20
- Date
- 2023
- Source
- Hepatology (Baltimore, Md.) 78(1): 167-178 (Journal)
- Registered Authors
- He, Jianbo, Luo, Lingfei
- Keywords
- none
- MeSH Terms
-
- Animals
- DNA (Cytosine-5-)-Methyltransferase 1
- Epithelial Cells
- Hepatocytes/physiology
- Humans
- Liver
- Liver Regeneration*/genetics
- Mechanistic Target of Rapamycin Complex 1
- Zebrafish*
- Zebrafish Proteins/genetics
- PubMed
- 36724876 Full text @ Hepatology
Citation
Ma, J., Yang, Z., Huang, Z., Li, L., Huang, J., Chen, J., Ni, R., Luo, L., He, J. (2023) Rngtt governs biliary-derived liver regeneration initiation by transcriptional regulation of mTORC1 and Dnmt1 in zebrafish. Hepatology (Baltimore, Md.). 78(1):167-178.
Abstract
In cases of end-stage liver diseases, the proliferation of existing hepatocytes is compromised, a feature of human chronic liver disease, in which most hepatocytes are dysfunctional. So far, liver transplantation represents the only curative therapeutic solution for advanced liver diseases, and the shortage of donor organs leads to high morbidity and mortality worldwide. The promising treatment is to prompt the biliary epithelial cells (BECs) transdifferentiation. However, the critical factors governing the initiation of BEC-derived liver regeneration are largely unknown. The zebrafish has advantages in large-scale genetic screens to identify the critical factors involved in liver regeneration. Here, we combined N-ethyl-N-nitrosourea screen, positional cloning, transgenic lines, antibody staining, and in situ hybridization methods and identified a liver regeneration defect mutant (lrd) using the zebrafish extensive liver injury model. Through positional cloning and genomic sequencing, we mapped the mutation site to rngtt. Loss of rngtt leads to the defects of BEC dedifferentiation, bipotential progenitor cell activation, and cell proliferation in the initiation stage of liver regeneration. The transdifferentiation from BECs to hepatocytes did not occur even at the late stage of liver regeneration. Mechanically, Rngtt transcriptionally regulates the attachment of mRNA cap to mTOR complex 1 (mTORC1) components and dnmt1 to maintain the activation of mTORC1 and DNA methylation in BECs after severe liver injury and prompt BEC to hepatocyte conversion. Furthermore, rptor and dnmt1 mutants displayed the same liver regeneration defects as rngtt mutation. In conclusion, our results suggest Rngtt is a new factor that initiates BEC-derived liver regeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping