title: Polycomb group protein Ezh2 regulates hepatic progenitor cell proliferation and differentiation in murine embryonic liver.
abstract: In embryonic liver, hepatic progenitor cells are actively proliferating and generate a fundamental cellular pool for establishing parenchymal components. However, the molecular basis for the expansion of the progenitors maintaining their immature state remains elusive. Polycomb group proteins regulate gene expression throughout the genome by modulating of chromatin structure and play crucial roles in development. Enhancer of zeste homolog 2 (Ezh2), a key component of polycomb group proteins, catalyzes tri-methylation of lysine 27 of histone H3 (H3K27me3), which trigger the gene suppression. In the present study, we investigated a role of Ezh2 in the regulation of the expanding hepatic progenitor population in vivo. We found that Ezh2 is highly expressed in the actively proliferating cells at the early developmental stage. Using a conditional knockout mouse model, we show that the deletion of the SET domain of Ezh2, which is responsible for catalytic induction of H3K27me3, results in significant reduction of the total liver size, absolute number of liver parenchymal cells, and hepatic progenitor cell population in size. A clonal colony assay in the hepatic progenitor cells directly isolated from in vivo fetal livers revealed that the bi-potent clonogenicity was significantly attenuated by the Ezh2 loss of function. Moreover, a marker expression based analysis and a global gene expression analysis showed that the knockout of Ezh2 inhibited differentiation to hepatocyte with reduced expression of a number of liver-function related genes. Taken together, our results indicate that Ezh2 is required for the hepatic progenitor expansion in vivo, which is essential for the functional maturation of embryonic liver, through its activity for catalyzing H3K27me3.
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ouchi
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Obana
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Zheng
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan; Project Leader of Advanced Medical Research Center, Yokohama City University, Kanazawa-ku, Yokohama, Kanagawa, Japan; PRESTO, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Takebe
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Isono
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan; Project Leader of Advanced Medical Research Center, Yokohama City University, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2