The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells
The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells
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DOI：
10.1016/j.jhep.2010.01.027
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发表时间：
2010-06-01
影响因子：
25.7
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
--
作者：
Aoki, Ryutaro;Chiba, Tetsuhiro;Iwama, Atsushi
背景与目的：多梳蛋白通过染色质修饰启动和维持基因沉默，并有助于维持多种干细胞的自我更新。在多梳抑制复合体中，PRC2通过甲基化组蛋白H3赖氨酸27来启动基因沉默，而PRC1通过组蛋白H_2A赖氨酸119的单一泛素化来维持基因沉默。我们先前已经证明，PRC1的核心成分Bmi1严格调控肝干/祖细胞的自我更新。方法：在本研究中，我们通过慢病毒介导的Ezh2基因敲除了PRC2的主要成分Ezh2在肝干/祖细胞中的功能。结果：胚胎小鼠肝干/祖细胞中Ezh2功能的丧失严重损害了增殖和自我更新能力。这一作用比Bmi1基因敲除更显著，并被PrC1和PrC2的主要靶标Ink4a和Arf的缺失部分取消。重要的是，Ezh2基因敲除而不是Bmi1基因敲除促进了肝细胞的分化和终末成熟，随后上调了几种肝细胞分化的转录调节因子。结论：Ezh2在维持肝干/祖细胞的增殖和自我更新能力以及充分执行其分化过程中起重要作用。(C)2010年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
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.