miR17~92 restrains pro-apoptotic BIM to ensure survival of haematopoietic stem and progenitor cells
miR17~92 restrains pro-apoptotic BIM to ensure survival of haematopoietic stem and progenitor cells
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DOI：
10.1038/s41418-019-0430-6
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发表时间：
2020-05-01
影响因子：
12.4
通讯作者：
Herold, Marco J.
中科院分区：
文献类型：
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作者：
Brinkmann, Kerstin;Ng, Ashley P.;Herold, Marco J.
miR17~92簇在造血过程中发挥重要作用。然而，目前尚不清楚miR17~92在什么分化阶段以及通过哪些靶标发挥这一功能。因此，我们生成了miR17~92(fl/fl)； RosaCreERT2 小鼠造血细胞中 miR17~92 的诱导缺失。骨髓重建实验表明，miR17~92缺失的细胞无法形成成熟的造血谱系，这是由于造血干/祖细胞（HSPC）的缺陷所致。为了确定 miR17~92 靶向的关键因子，我们在 HSPC 中进行了基因表达分析，证明促凋亡 Bim 的 mRNA 水平与 miR17~92 簇的表达呈负相关。引人注目的是，促凋亡 BIM 的丢失完全阻止了因 miR17~92 删除而导致的 HSPC 丢失。 BIM/miR17~92 相互作用在人 CD34(+) HSPC 中是保守的，因为 miR17~92 抑制或阻断其与 BIM 3' UTR 的结合会降低这些细胞的存活和生长。尽管预测 miR17~92 通过影响大量不同靶点发挥作用，但仅缺乏 BIM 就足以防止造血细胞中因删除 miR17~92 引起的所有缺陷。
The miR17~92 cluster plays important roles in haematopoiesis. However, it is not clear at what stage of differentiation and through which targets miR17~92 exerts this function. Therefore, we generated miR17~92(fl/fl); RosaCreERT2 mice for inducible deletion of miR17~92 in haematopoietic cells. Bone marrow reconstitution experiments revealed that miR17~92-deleted cells were not capable to contribute to mature haematopoietic lineages, which was due to defects in haematopoietic stem/progenitor cells (HSPCs). To identify the critical factor targeted by miR17~92 we performed gene expression analysis in HSPCs, demonstrating that mRNA levels of pro-apoptotic Bim inversely correlated with the expression of the miR17~92 cluster. Strikingly, loss of pro-apoptotic BIM completely prevented the loss of HSPCs caused by deletion of miR17~92. The BIM/miR17~92 interaction is conserved in human CD34(+) HSPCs, as miR17~92 inhibition or blockade of its binding to the BIM 3 ' UTR reduced the survival and growth of these cells. Despite the prediction that miR17~92 functions by impacting a plethora of different targets, the absence of BIM alone is sufficient to prevent all defects caused by deletion of miR17~92 in haematopoietic cells.