Regulation of embryonic haematopoietic multipotency by EZH1.
Regulation of embryonic haematopoietic multipotency by EZH1.
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通过EZH1调节胚胎造血多重性。
DOI：
10.1038/nature25435
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发表时间：
2018-01-25
期刊：
影响因子：
64.8
通讯作者：
Daley GQ
中科院分区：
文献类型：
--
作者：
Vo LT;Kinney MA;Liu X;Zhang Y;Barragan J;Sousa PM;Jha DK;Han A;Cesana M;Shao Z;North TE;Orkin SH;Doulatov S;Xu J;Daley GQ
在成年哺乳动物血液中循环的所有造血谱系都来源于多能造血干细胞（HSC）。哺乳动物胚胎中的造血形成鲜明对比，谱系限制的祖细胞首先出现，独立于HSC，而HSC仅在妊娠后期出现。正如在小鼠中最好地定义的那样，“原始”祖细胞在交配后7.5天（dpc）首次出现在卵黄囊（YS）中。随后，表达胎儿血红蛋白的红系-髓系祖细胞（EMP）以及胎儿淋巴样祖细胞在YS和胚胎中发育，但这些细胞缺乏HSC潜能。最终，在10.5 dpc时，具有长期、多系潜能和植入辐照成人的能力的“确定性”HSC从动脉内皮在性腺中肾（AGM）和其他造血血管系统中出现。造血个体发育的逆转进展的分子机制仍然无法解释。我们假设，明确的造血程序可能会积极抑制在早期胚胎发生通过表观遗传沉默，减轻这种抑制将引发多能性，否则限制造血祖细胞。在这里，我们证明，减少表达的Polycomb组蛋白EZH 1揭示了多淋巴输出从人类多能干细胞（PSC）和早熟出现的功能性永久性HSC在网站的原始和/或EMP偏向体内造血，确定EZH 1作为一个阻遏物的造血多能性在早期哺乳动物胚胎。
All haematopoietic lineages circulating in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs). Haematopoiesis in the mammalian embryo stands in stark contrast, with lineage-restricted progenitors arising first, independently of HSCs, and HSCs emerging only later in gestation. As best defined in the mouse, “primitive” progenitors first appear in the yolk sac (YS) at 7.5 days post-coitum (dpc). Subsequently, erythroid-myeloid progenitors (EMPs) that express fetal hemoglobin, as well as fetal lymphoid progenitors develop in the YS and the embryo proper, but these cells lack HSC potential. Ultimately, “definitive” HSCs with long-term, multilineage potential and the capacity to engraft irradiated adults emerge at 10.5 dpc from arterial endothelium in the aorta-gonad-mesonephros (AGM) and other haemogenic vasculature. The molecular mechanisms for reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis via epigenetic silencing, and that alleviating this repression would elicit multipotency in otherwise restricted haematopoietic progenitors. Here, we demonstrate that reduced expression of the Polycomb group protein EZH1 uncovers multi-lymphoid output from human pluripotent stem cells (PSCs) and precocious emergence of functional definitive HSCs at sites of primitive and/or EMP-biased haematopoiesis in vivo, identifying EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.
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影响因子：
30.5
作者：
Laurenti E;Doulatov S;Zandi S;Plumb I;Chen J;April C;Fan JB;Dick JE
通讯作者：
Dick JE
影响因子：
23.9
作者：
Doulatov, Sergei;Vo, Linda T.;Chou, Stephanie S.;Kim, Peter G.;Arora, Natasha;Li, Hu;Hadland, Brandon K.;Bernstein, Irwin D.;Collins, James J.;Zon, Leonard I.;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
8.8
作者：
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影响因子：
21.3
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通讯作者：
Keller G
影响因子：
20.3
作者：
Jang, Il Ho;Lu, Yi-Fen;Daley, George Q.
通讯作者：
Daley, George Q.