Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Blood. 2011 Aug 25;118(8):2275-84. doi: 10.1182/blood-2011-02-335141. Epub 2011 Jul 5.
The differentiation of HSCs into myeloid lineages requires the transcription factor PU.1. Whereas PU.1-dependent induction of myeloid-specific target genes has been intensively studied, negative regulation of stem cell or alternate lineage programs remains incompletely characterized. To test for such negative regulatory events, we searched for PU.1-controlled microRNAs (miRs) by expression profiling using a PU.1-inducible myeloid progenitor cell line model. We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. Ectopic expression of the most robustly induced PU.1 target miR, miR-146a, directed the selective differentiation of HSCs into functional peritoneal macrophages in mouse transplantation assays. In agreement with this observation, disruption of Dicer expression or specific antagonization of miR-146a function inhibited the formation of macrophages during early zebrafish (Danio rerio) development. In the present study, we describe a PU.1-orchestrated miR program that mediates key functions of PU.1 during myeloid differentiation.
造血干细胞向髓系分化需要转录因子 PU.1。虽然已经深入研究了 PU.1 依赖性诱导髓系特异性靶基因，但干细胞或替代谱系程序的负调控仍未完全描述。为了测试这种负调控事件，我们使用 PU.1 诱导的髓系祖细胞系模型通过表达谱筛选寻找 PU.1 控制的 microRNAs (miRs)。我们提供的证据表明，PU.1 通过在其基因组编码基因座附近的调节染色质区域内的结合位点的动态占据，直接控制至少 4 种这些 miRs（miR-146a、miR-342、miR-338 和 miR-155）的表达。最强烈诱导的 PU.1 靶 miR miR-146a 的异位表达在小鼠移植实验中指导 HSCs 选择性分化为功能性腹膜巨噬细胞。与这一观察结果一致，破坏 Dicer 表达或特异性拮抗 miR-146a 功能抑制了早期斑马鱼（Danio rerio）发育过程中巨噬细胞的形成。在本研究中，我们描述了一个由 PU.1 协调的 miR 程序，该程序介导了 PU.1 在髓系分化过程中的关键功能。
