Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells.
Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells.
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DOI：
10.1016/j.cell.2008.12.043
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发表时间：
2009-03-20
期刊：
影响因子：
64.5
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Ezhkova E;Pasolli HA;Parker JS;Stokes N;Su IH;Hannon G;Tarakhovsky A;Fuchs E
尽管胚胎干细胞的体外研究已经确定多梳阻遏复合物（PRC）是分化的关键调节因子，但PRC介导的机制如何控制发育组织中多能祖细胞的命运仍不清楚。在这里，我们发现PRC的一个重要成分Ezh2在表皮祖细胞中表达，但随着胚胎分化和出生后增殖活性的下降而减少。我们发现，Ezh2 通过抑制 Ink4A-Ink4B 基因座来控制基底祖细胞的增殖潜力，并通过防止 AP1 转录激活因子过早募集到表皮分化所需的结构基因来调节分化的发育速率。总之，我们的研究表明，PRC 在组织限制性干细胞中在时间和空间上控制表观遗传修饰。它们保持增殖潜力并全局抑制不需要的分化程序，同时以逐步方式选择性地建立特定的终末分化程序。
Although in vitro studies of embryonic stem cells have identified polycomb repressor complexes (PRCs) as key regulators of differentiation, it remains unclear as to how PRC-mediated mechanisms control fates of multipotent progenitors in developing tissues. Here, we show that an essential PRC component, Ezh2, is expressed in epidermal progenitors but diminishes concomitant with embryonic differentiation and with postnatal decline in proliferative activity. We show that Ezh2 controls proliferative potential of basal progenitors by repressing the Ink4A-Ink4B locus and tempers the developmental rate of differentiation by preventing premature recruitment of AP1 transcriptional activator to the structural genes that are required for epidermal differentiation. Together, our studies reveal that PRCs control epigenetic modifications temporally and spatially in tissue-restricted stem cells. They maintain their proliferative potential and globally repressing undesirable differentiation programs while selectively establishing a specific terminal differentiation program in a stepwise fashion.
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