MicroRNA programs in normal and aberrant stem and progenitor cells

Emerging evidence suggests that microRNAs (miRNAs), an abundant class of ~22-nt small regulatory RNAs, play key roles in controlling the post-transcriptional genetic programs in stem and progenitor cells. Here we systematically examined miRNA expression profiles in various adult tissue-specific stem cells and their differentiated counterparts. These analyses revealed miRNA programs that are common or unique to blood, muscle, and neural stem cell populations and miRNA signatures that mark the transitions from self-renewing and quiescent stem cells to proliferative and differentiating progenitor cells. Moreover, we found a stem/progenitor transition miRNA (SPT-miRNA) signature that predicts the effects of genetic perturbations, such as loss of PTEN and the Rb family, AML-ETO expression, and MLL-AF10 transformation, on self-renewal, proliferation, and/or differentiation potentials of mutant stem/progenitor cells. More importantly, some SPT-miRNAs can control rate of self-renewal in embryonic stem cells and the reconstitution potential of hematopoietic stem cells (HSCs). Finally, we found that some SPT-miRNAs may coordinately regulate genes that are known to play roles in controlling HSC self-renewal, such as Hoxb6 and Hoxa4. Together, these analyses revealed the miRNA programs that control key processes in normal and aberrant stem and progenitor cells, setting the foundations for dissecting post-transcriptional regulatory networks in stem cells. We used a multiplex protocol to amplify miRNAs from 20-1000 sorted stem and/or progenitor cells and then analyzed the expression of 425 mature miRNAs using TaqMan miRNA quantitative PCR analyses

越来越多的研究证据表明，微小RNA（miRNAs）——一类丰度较高的~22核苷酸小型调控RNA——在调控干细胞与祖细胞的转录后遗传程序中发挥关键作用。本研究系统检测了多种组织特异性成体干细胞及其分化对应细胞群中的miRNA表达谱。
这些分析揭示了血液、肌肉及神经干细胞群体共有的或特异性的miRNA调控程序，以及标记从自我更新且静息的干细胞向增殖并具备分化能力的祖细胞转变过程的miRNA特征标记。此外，本研究发现了一类干细胞/祖细胞转换相关微小RNA（SPT-miRNA）特征标记，其可预测遗传扰动——如PTEN缺失、Rb家族基因缺失、AML-ETO融合基因表达以及MLL-AF10融合基因转化——对突变干细胞/祖细胞的自我更新、增殖和/或分化潜能的影响。
更为重要的是，部分SPT-miRNAs可调控胚胎干细胞的自我更新速率以及造血干细胞（HSCs）的重建潜能。最后，本研究发现部分SPT-miRNAs可协同调控已知参与造血干细胞自我更新调控的基因，如Hoxb6与Hoxa4。
综上，本研究的分析揭示了调控正常与异常干细胞及祖细胞关键过程的miRNA调控程序，为解析干细胞内的转录后调控网络奠定了基础。本研究采用多重扩增实验方案，从20至1000个分选得到的干细胞和/或祖细胞中扩增miRNAs，随后通过TaqMan微小RNA定量PCR分析了425种成熟miRNA的表达水平。