The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells

JOURNAL OF HEPATOLOGY

卷:52

Article

Aoki, Ryutaro^1,2  Chiba, Tetsuhiro^1,2,3  Miyagi, Satoru¹  Negishi, Masamitsu¹  Konuma, Takaaki¹  Taniguchi, Hideki⁴  Ogawa, Makoto²  Yokosuka, Osamu²  Iwama, Atsushi^1,3 

[1] Chiba Univ, Grad Sch Med, Dept Cellular & Mol Med, Chuo Ku, Chiba 2608670, Japan

[2] Chiba Univ, Grad Sch Med, Dept Med & Clin Oncol, Chuo Ku, Chiba 2608670, Japan

[3] CREST, JST, Chiyoda Ku, Tokyo 1020075, Japan

[4] Yokohama City Univ, Grad Sch Med, Dept Regenerat Med, Kanazawa Ku, Kanagawa 2360004, Japan

关键词: Hepatic stem/progenitor cells;    Ezh2;    Bmi1;    Ink4a/Arf;    Self-renewal;    Differentiation;   

DOI  :  10.1016/j.jhep.2010.01.027

来源: Elsevier

【 摘 要 】

Background & Aims: Polycomb group proteins initiate and maintain gene silencing through chromatin modifications and contribute to the maintenance of self-renewal in a variety of stem cells. Among polycomb repressive complexes (PRCs), PRC2 initiates gene silencing by methylating histone H3 lysine 27, and PRC1 maintains gene silencing through mono-ubiquitination of histone H2A lysine 119. We have previously shown that Bmi1, a core component of PRC1, tightly regulates the self-renewal of hepatic stem/progenitor cells. Methods: In this study, we conducted lentivirus-mediated knockdown of Ezh2 to characterise the function of Ezh2, a major component of PRC2, in hepatic stem/progenitor cells. Results: Loss of Ezh2 function in embryonic murine hepatic stem/progenitor cells severely impaired proliferation and self-renewal capability. This effect was more prominent than that of Bmi1-knockdown and was partially abrogated by the deletion of both Ink4a and Arf, major targets of PRC1 and PRC2. Importantly, Ezh2-knockdown but not Bmi1-knockdown promoted the differentiation and terminal maturation of hepatocytes, followed by the up-regulation of several transcriptional regulators of hepatocyte differentiation. Conclusions: Our findings indicate that Ezh2 plays an essential role in the maintenance of both the proliferative and self-renewal capacity of hepatic stem/progenitor cells and the full execution of their differentiation. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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