Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells
Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells
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DOI：
10.1182/blood-2011-03-340554
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发表时间：
2011-12-15
期刊：
影响因子：
20.3
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
--
作者：
Mochizuki-Kashio, Makiko;Mishima, Yuta;Iwama, Atsushi
多梳族蛋白（Polycomb-group，PcG）是造血干细胞（hematopoietic stem cells，HSC）的重要调节因子。与Polycomb抑制复合物1（PRC 1）的成分Bmi 1相反，PRC 2及其成分在造血中的作用仍然难以捉摸。在这里，我们表明，Ezh 2，PRC 2的核心组成部分，是必不可少的胎儿，但不是成人，造血干细胞。Ezh 2缺陷胚胎由于造血干细胞/祖细胞扩增不足和胎肝红细胞生成缺陷而死于贫血。然而，在成人骨髓中Ezh 2的缺失并没有显著损害造血，除了淋巴细胞生成。值得注意的是，Ezh 2缺陷的胎肝细胞显示组蛋白H3在赖氨酸27处的三甲基化（H3 K27 me 3）急剧减少，伴随着大量基因的去阻遏，而在归巢到BM时，它们获得了高水平的H3 K27 me 3和长期的再增殖能力。定量RTPCR显示，Ezh 1，基因编码的备份酶，是高表达的造血干细胞/祖细胞在骨髓相比，在胎肝，而Ezh 2是普遍表达。这些发现表明，Ezh 1补充Ezh 2在骨髓中，但不是在胎儿肝脏，并揭示了加强PcG介导的基因沉默发生在从增殖的胎儿HSC的过渡到静止的成人HSC。（血。2011; 118（25）：6553-6561）
Polycomb-group (PcG) proteins are essential regulators of hematopoietic stem cells (HSCs). In contrast to Bmi1, a component of Polycomb repressive complex 1 (PRC1), the role of PRC2 and its components in hematopoiesis remains elusive. Here we show that Ezh2, a core component of PRC2, is essential for fetal, but not adult, HSCs. Ezh2-deficient embryos died of anemia because of insufficient expansion of HSCs/progenitor cells and defective erythropoiesis in fetal liver. Deletion of Ezh2 in adult BM, however, did not significantly compromise hematopoiesis, except for lymphopoiesis. Of note, Ezh2deficient fetal liver cells showed a drastic reduction in trimethylation of histone H3 at lysine 27 (H3K27me3) accompanied by derepression of a large cohort of genes, whereas on homing to BM, they acquired a high level of H3K27me3 and long-term repopulating capacity. Quantitative RTPCR revealed that Ezh1, the gene encoding a backup enzyme, is highly expressed in HSCs/progenitor cells in BM compared with those in fetal liver, whereas Ezh2 is ubiquitously expressed. These findings suggest that Ezh1 complements Ezh2 in the BM, but not in the fetal liver, and reveal that the reinforcement of PcGmediated gene silencing occurs during the transition from proliferative fetal HSCs to quiescent adult HSCs. (Blood. 2011; 118(25): 6553-6561)