The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Cell Death Differ. 2020 May;27(5):1475-1488. doi: 10.1038/s41418-019-0430-6. Epub 2019 Oct 7.
The miR1792 cluster plays important roles in haematopoiesis. However, it is not clear at what stage of differentiation and through which targets miR1792 exerts this function. Therefore, we generated miR1792; RosaCreERT2 mice for inducible deletion of miR1792 in haematopoietic cells. Bone marrow reconstitution experiments revealed that miR1792-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 miR1792 we performed gene expression analysis in HSPCs, demonstrating that mRNA levels of pro-apoptotic Bim inversely correlated with the expression of the miR1792 cluster. Strikingly, loss of pro-apoptotic BIM completely prevented the loss of HSPCs caused by deletion of miR1792. The BIM/miR1792 interaction is conserved in human CD34 HSPCs, as miR1792 inhibition or blockade of its binding to the BIM 3'UTR reduced the survival and growth of these cells. Despite the prediction that miR1792 functions by impacting a plethora of different targets, the absence of BIM alone is sufficient to prevent all defects caused by deletion of miR1792 in haematopoietic cells.
miR1792 簇在造血中起着重要作用。然而，miR1792 是在分化的哪个阶段通过哪些靶基因发挥作用尚不清楚。因此，我们生成了 miR1792; RosaCreERT2 小鼠，用于诱导造血细胞中 miR1792 的缺失。骨髓重建实验表明，miR1792 缺失的细胞不能分化为成熟的造血谱系，这是由于造血干细胞/祖细胞 (HSPCs) 存在缺陷。为了确定 miR1792 靶向的关键因子，我们在 HSPCs 中进行了基因表达分析，结果表明促凋亡因子 Bim 的 mRNA 水平与 miR1792 簇的表达呈负相关。令人惊讶的是，缺失促凋亡的 BIM 完全阻止了 miR1792 缺失导致的 HSPCs 缺失。BIM/miR1792 相互作用在人类 CD34 HSPCs 中是保守的，因为 miR1792 抑制或阻断其与 BIM 3'UTR 的结合，降低了这些细胞的存活和生长。尽管预测 miR1792 通过影响众多不同的靶基因发挥作用，但单独缺失 BIM 足以防止 miR1792 在造血细胞中缺失引起的所有缺陷。
