Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells
Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells
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DOI：
10.1016/j.exphem.2015.12.009
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发表时间：
2016-04-01
影响因子：
2.6
通讯作者：
Iwamaa, Atsushi
中科院分区：
文献类型：
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作者：
Oshima, Motohiko;Hasegawa, Nagisa;Iwamaa, Atsushi
胚胎肝造血干细胞（HSCs）种子骨髓（BM），并经历重编程成成人型造血干细胞，这些造血干细胞在很大程度上是静止的，其自我更新活性受到限制。在缺少多巢群基因Ezh2的情况下，一组胎儿特异性基因，包括let-7靶基因，在骨髓造血干细胞（HSPCs）中被激活，导致骨髓造血干细胞获得胎儿表型，如增强自我更新活性和胎儿型淋巴细胞的产生。Lin28b/let-7通路决定HSPC程序的发育时间变化。值得注意的是，许多胎儿特异性的let-7靶基因，包括Lin28，似乎在BM HSPCs中被Ezh2介导的H3K27me3转录抑制，Ezh2缺失导致它们的异位表达，特别是在缺乏Ezh2的血液恶性肿瘤中。这些发现表明Ezh2与let-7 microrna协同沉默BM HSPCs中的胎儿基因标记并限制其转化。版权所有2016 ISEH -国际实验血液学学会Elsevier Inc.出版。
Fetal liver hematopoietic stem cells (HSCs) seed bone marrow (BM) and undergo reprograming into adult-type HSCs that are largely quiescent and restricted in their self-renewal activity. Here we report that in the absence of the polycomb-group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem/progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b/let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appear to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss results in their ectopic expression, particularly in hematologic malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing the fetal gene signature in BM HSPCs and restricts their transformation. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.