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首页> 外文期刊>PLoS Genetics >The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis
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The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis

机译：miR-23a〜27a〜24-2 microRNA簇在造血过程中缓冲转录和信号通路

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MicroRNA cluster mirn23a has previously been shown to promote myeloid development at the expense of lymphoid development in overexpression and knockout mouse models. This polarization is observed early in hematopoietic development, with an increase in common lymphoid progenitors (CLPs) and a decrease in all myeloid progenitor subsets in adult bone marrow. The pool size of multipotential progenitors (MPPs) is unchanged; however, in this report we observe by flow cytometry that polarized subsets of MPPs are changed in the absence of mirn23a. Additionally, in vitro culture of MPPs and sorted MPP transplants showed that these cells have decreased myeloid and increased lymphoid potential in vitro and in vivo. We investigated the mechanism by which mirn23a regulates hematopoietic differentiation and observed that mirn23a promotes myeloid development of hematopoietic progenitors through regulation of hematopoietic transcription factors and signaling pathways. Early transcription factors that direct the commitment of MPPs to CLPs (Ikzf1, Runx1, Satb1, Bach1 and Bach2) are increased in the absence of mirn23a miRNAs as well as factors that commit the CLP to the B cell lineage (FoxO1, Ebf1, and Pax5). Mirn23a appears to buffer transcription factor levels so that they do not stochastically reach a threshold level to direct differentiation. Intriguingly, mirn23a also inversely regulates the PI3 kinase (PI3K)/Akt and BMP/Smad signaling pathways. Pharmacological inhibitor studies, coupled with dominant active/dominant negative biochemical experiments, show that both signaling pathways are critical to mirn23a’s regulation of hematopoietic differentiation. Lastly, consistent with mirn23a being a physiological inhibitor of B cell development, we observed that the essential B cell transcription factor EBF1 represses expression of mirn23a. In summary, our data demonstrates that mirn23a regulates a complex array of transcription and signaling pathways to modulate adult hematopoiesis.
机译：在过表达和基因敲除小鼠模型中，MicroRNA簇mirn23a先前已显示出促进髓样发育，但以淋巴样发育为代价。这种分化在造血发育的早期就可以观察到，成年骨髓中常见的淋巴祖细胞（CLP）增多​​，而所有髓样祖细胞亚群减少。多能祖细胞（MPP）的库大小保持不变;但是，在本报告中，我们通过流式细胞术观察到在没有mirn23a的情况下，MPP的极化子集发生了变化。此外，MPP和分选的MPP移植物的体外培养表明，这些细胞在体外和体内均具有减少的髓样和增加的淋巴样潜能。我们研究了mirn23a调节造血分化的机制，并观察到mirn23a通过调节造血转录因子和信号通路来促进造血祖细胞的骨髓发育。在缺少mirn23a miRNA的情况下，引导MPP对CLP承诺的早期转录因子（Ikzf1，Runx1，Satb1，Bach1和Bach2）以及将CLP提交给B细胞谱系的因子（FoxO1，Ebf1和Pax5）都会增加。 ）。 Mirn23a似乎可以缓冲转录因子的水平，因此它们不会随机达到指导分化的阈值水平。有趣的是，mirn23a还反向调节PI3激酶（PI3K）/ Akt和BMP / Smad信号通路。药理抑制剂研究与显性的活性/显性阴性生化实验相结合，表明这两种信号通路对于mirn23a调节造血分化至关重要。最后，与mirn23a是B细胞发育的生理抑制剂一致，我们观察到必需的B细胞转录因子EBF1抑制mirn23a的表达。总而言之，我们的数据表明mirn23a调控着一系列复杂的转录和信号传导途径，以调节成人造血功能。

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