Background: Polycomb group protein enhancer of zeste homolog 2 (EZH2) controls cell proliferation and differentiation and is frequently up-regulated in hepatocellular carcinoma. Genetic inactivation of Ezh2 did not produce obvious phenotypic differenc...
Background: Polycomb group protein enhancer of zeste homolog 2 (EZH2) controls cell proliferation and differentiation and is frequently up-regulated in hepatocellular carcinoma. Genetic inactivation of Ezh2 did not produce obvious phenotypic differences in knockout livers suggesting a functional redundancy with Ezh1 homolog. Methods: To investigate the role of both Ezh1 and Ezh2 in liver homeostasis, we generated double knockout mice (E1/2KO) by crossing Ezh1 null and albumin promoter- driven Ezh2 conditional-null mice.The combined loss of EZH1 and EZH2 in mouse hepatocytes caused a global and gene-specific depletion of H3K27me3 marks including genes associated with hepatocyte homeostasis and regeneration. Mice mutant for both Ezh1 and Ezh2 remained viable and overtly normal by 3 months of age. Thereafter, E1/2KO mice exhibited progressive liver abnormalities manifested by development of regenerative nodules and concomitant periportal fibrosis, infiammatory infiltration and activation of A6-positive hepatic progenitor cells (HPCs). Results: In response to chronic treatment with CCl4, E1/2KO mice showed increased hepatic degeneration associated with liver dysfunction, cholestasis, and reduced ability to proliferate. CCl4-induced hepatotoxicity triggered an activation of HPCs, which did not prevent early lethality of E1/2KO mice. After 2/3ds partial hepatectomy, E1/2KO livers showed an increased liver injury and a blunted regenerative response. RNA-seq analysis revealed dysregulation of genes related to regulation of cell survival, fibrosis, and proliferation including Cdkn2a and Cdkn2b. Conclusions: This work demonstrates a critical role of EZH1 and EZH2in maintaining hepatic homeostasis and ability to regenerate.