Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development
Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development
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在造血干细胞发育过程中，Notch1 表达在转录后水平受到 3 非翻译区的调节
DOI：
10.1007/s12185-017-2358-2
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发表时间：
2017
影响因子：
2.1
通讯作者：
Akashi Koichi
中科院分区：
文献类型：
--
作者：
Mizuno Shinichi;Iino Tadafumi;Ozawa Hidetoshi;Arinobu Yojiro;Chong Yong;Akashi Koichi
在造血过程中，关键基因的表达受到特定阶段的调节，以维持正常的造血功能。Notch1是参与T细胞谱系定型和发育的重要基因。然而，Notch1在造血过程中的调节存在争议，特别是在造血干细胞（HSC）水平上。在这里，我们发现Notch1的表达在HSC中受到转录后水平的控制。 HSC 表达相当水平的 Notch1 mRNA，但其蛋白水平非常低，表明 Notch1 存在转录后抑制。使用表达 GFP 和靶基因 3' 非翻译区 (3'UTR) 融合 mRNA 的逆转录病毒传感器载体，我们证明了 Notch1-3'UTR 仅在 HSC 中具有翻译后抑制作用，而在下游祖细胞阶段则没有。 Notch1-3'UTR 的转录后调节需要序列基序 AUnA。有趣的是，当HSC被放置在胸腺中而不是骨髓中时，这种Notch1-3'UTR介导的抑制作用得到缓解。因此，Notch1在HSC中的表达在转录后水平受到微环境的调节，这可能控制HSC的T淋巴谱系定型。
In hematopoiesis, the expression of critical genes is regulated in a stage-specific manner to maintain normal hematopoiesis.Notch1is an essential gene involved in the commitment and development of the T-cell lineage. However, the regulation ofNotch1in hematopoiesis is controversial, particularly at the level of hematopoietic stem cell (HSC). Here, we found that the expression ofNotch1is controlled at the post-transcriptional level in HSCs. HSCs express a considerable level ofNotch1mRNA, but its protein level is very low, suggesting a post-transcriptional suppression forNotch1. Using a retroviral sensor vector expressing a fusion mRNA of GFP and 3′ untranslated region (3′UTR) of a target gene, we demonstrated that theNotch1-3′UTR had a post-translational suppressive effect only at the HSC but not in the downstream progenitor stages. The sequence motif AUnA was required for this post-transcriptional regulation by theNotch1-3′UTR. Interestingly, thisNotch1-3′UTR-mediated suppressive effect was relieved when HSCs were placed in the thymus, but not in the bone marrow. Thus, the expression ofNotch1in HSCs is regulated by microenvironment at the post-transcriptional level, which may control T lymphoid lineage commitment from HSCs.