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Zinc Finger Protein 219(ZNF219) Regulates Hepatocyte-Conventional Natural Killer Cell Crosstalk and Hepatocyte Proliferation to Accelerate Liver Regeneration
24 Pages Posted: 14 May 2025
More...Abstract
Background: Zinc finger protein 219 (ZNF219) belongs to the family of Kruppel-like factors. It is known that ZNF219 functioned as a transcriptional regulator and contributed to chondrocyte differentiation and prevention of ROS-induced injury. Our preliminary data showed upregulation of ZNF219 during liver regeneration, whereas its role in this process has not been defined.
Methods: 70% partial hepatectomy (PHx) was performed on wildtype(WT) and ZNF219 knockout(ZNF219-/-) mice. Liver regeneration and injury were analyzed after PHx. AML12 cells, primary mouse hepatocytes and natural killer(NK) cells were used to explore underlying mechanisms.
Findings: ZNF219 removal markedly impaired liver regeneration. Increased infiltrated conventional natural killer cells(cNKs) and IFNγ-producing natural killer cells were detected in liver tissues of ZNF219-/- mice post-operation. Mechanistically, ZNF219 regulated natural killer cells via epigenetically repressing C-C motif chemokine ligand 5(CCL5) expression in hepatocytes through collaborating with lysine-specific demethylase1(LSD1). Neutralizing CCL5 abolished the infiltration and activation of natural killer cells. Furthermore, ZNF219 promotes cell cycle progression of hepatocyte post-operation. Interfering with ZNF219 resulted in downregulation of multiple genes involved in cell cycle and DNA replication in AML12 cells. One direct target of ZNF219 in regulating hepatocyte proliferation was Ki67, facilitating the recruitment of specificity protein 1(SP1) via interaction occurring downstream of ZNF219 in this process.
Interpretation: Our study revealed that ZNF219 acts as an accelerator in liver regeneration, functioned by remodeling intra-hepatic immune milieu and promoting cell cycle progression of hepatocyte.
Keywords: liver regeneration, ZNF219, conventional natural killer cells, cell cycle progression
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